The present invention relates to compounds which are non-peptidyl in structure and active as potent inhibitors of the binding of very late antigen-4 (VLA-4; xcex14xcex21; CD49d/CD29) to proteins such as vascular cell adhesion molecule-1 (VCAM-1), the HepII/IIICS domain (CS-1 region) of fibronectin and osteopontin. As such they are useful in the inhibition of cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4. The compounds and pharmaceutical compositions of this invention may be used in the treatment of many inflammatory, autoimmune and respiratory diseases, especially asthma.
One of the most fundamental processes necessary for normal host defence is the regulated trafficking of leukocytes out of the vasculature. This system is designed to allow normal recirculation of leukocytes, yet because it enables the rapid extravasation of leukocytes at sites of injury it is one of the central pathogenic mechanisms of inflammatory, respiratory and autoimmune diseases in mammals. Cell adhesion is a key factor in this process, and it is particularly relevant to the present invention regarding the cell/cell and cell/matrix binding of hematopoietic cells containing VLA-4.
VLA-4 is a member of a superfamily of cell surface macromolecular receptors called integrins, which are non-covalent heterodimeric complexes consisting of an xcex1 subunit and a xcex2 subunit (Hemler, Ann. Rev. Immunol., 8, p.365, 1990). Eighteen different xcex1 subunits have been identified and labeled xcex11-xcex110, xcex1L, xcex1M, xcex1x, xcex1d, xcex1LRI, xcex1IIB, xcex1V, and xcex1E; while eight different xcex2 subunits have been identified and labeled xcex21-xcex28. Each integrin molecule can be categorized into a subfamily based on the type of its xcex1 and xcex2 subunits. The xcex14xcex21 integrin, VLA-4, is an integrin constitutively expressed by all leukocytes (e.g., monocytes, lymphocytes, basophils, eosinophils, mast cells and macrophages) except polymorphonuclear leukocytes. The binding of this integrin to one of its ligands has a number of known cell adhesion and activation functions (Hemler, Ann. Rev. Immunol., 8, p.365, 1990; Walsh et al., Clin. and Exp. Allergy, 25, p. 1128, 1995; Huhtala et al., J. Cell Biol., 129, p. 867, 1995). In particular, it is a receptor for the cytokine-inducible endothelial cell surface protein known as vascular cell adhesion molecule-1 (VCAM-1), for the alternatively spliced forms of the extracellular matrix protein fibronectin (FN) containing the CS-1 domain (Ruegg et al., J. Cell Biol., 177, p. 179, 1991; Wayner et al., J. Cell Biol., 105, p. 1873, 1987; Kramer et al., J. Biol. Chem., 264, p.4684, 1989; Gehlsen et al., Science, 24, p. 1228, 1988) and for the extracellular matrix protein osteopontin (Bayless, K. I. et al. J. Cell Science, 111, p. 1165-1174, 1998). The importance of VLA-4 cell adhesion interactions has been established by the use of specific monoclonal antibody (mAb) antagonists of the a subunit of VLA-4, which have demonstrated that inhibitors of VLA-4 dependent cell adhesion prevent or inhibit numerous inflammatory, respiratory and autoimmune pathological conditions (Chisholm et al., Eur. J. Immunol., 23, p. 682, 1993; Lobb et al., J. Clin. Invest, 94, p. 1722, 1994; Richards et al., Am. J. Respir. Cell Mol. Biol., 15, p.172, 1996; Soiluhanninen et al., J. Neuroimmunol., 72, p. 95, 1997; Sagara et al., Int. Arch. Allergy Immunol., 112, p.287, 1997; Fryer et al., J. Clin. Invest., 99, p. 2036, 1997). In addition, confirmation that this pathological processes can be inhibited with agents other than antibodies has been observed in animal models following treatment with a synthetic CS-1 peptide or a small molecule peptide inhibitor of VLA-4 (Ferguson et al., Proc. Natl. Acad. Sci., 88, p.8072, 1991; Wahl et al., J. Clin. Invest., 94, p.655, 1994; Molossi et al., J. Clin. Invest., 95, p.2601, 1995; Abraham et al., Am. J. Respir. Crit. Care Med., 156, p. 696, 1997; Jackson et al., J. Med. Chem., 40, p. 3359, 1997).
3.0 Description of the State of the Art
The investigation of mAb and peptide VLA-4 antagonists in the art has already been noted above. In defining the binding site for xcex14xcex21 it has been observed that lymphoid cells can bind to two different sites on fibronectin (Bernardi et al., J. Cell Biol., 105, p. 489, 1987). One component of this cell binding activity has previously been identified as the tripeptide Arg-Gly-Asp (RGD) that binds to the integrin xcex15xcex21 (VLA5). Subsequently, the minimum amino acid sequence required to bind and antagonize the activity of VLA-4 on leukocytes to the alternatively spliced site in fibronectin was determined (Humphries et al., J. Biol. Chem., 266, p.6886, 1987; Garcia-Pardo et al., J. Immunol., 144, p.3361, 1990; Komoriya et al., J. Biol. Chem., 266, p. 15075, 1991). It has been discovered that the VLA-4 binding domain in the CS-1 region of fibronectin (FN) comprises the octapeptide: Glu-Ile-Leu-Asp-Val-Pro-Ser-Thr, as well as two overlapping pentapeptides: Glu-Ile-Leu-Asp-Val and Leu-Asp-Val-Pro-Ser. All of these peptides inhibit FN-dependent cell adhesion, leading to the early conclusion that the minimal amino acid sequence required for inhibition would be Leu-Asp-Val (LDV). In fact the LDV minimal inhibitory sequence has been observed to be equally effective as the full length CS-1 fragment in binding the activated form of VLA-4 (Wayner et al., J. Cell Biol., 116, p. 489, 1992).
Various integrins are believed to bind to extracellular matrix proteins at an Arg-Gly Asp (RGD) recognition site. RGD based cyclic peptides have been made that are said to be able to inhibit both xcex14xcex21 and xcex15xcex21 binding to FN (Nowlin et al., J. Biol. Chem., 268, p. 20352, 1993; PCT/US91/04862) even though the primary recognition on FN for xcex14xcex21 is LDV. The cyclic peptide may be represented by Formula (0.0.1): 
where TPro denotes 4-thioproline.
Other peptidyl inhibitors of VLA-4 are those referred to in Arrhenius et al., xe2x80x9cCS-1 Peptidomimetics,xe2x80x9d WO 95/15973, which is assigned to the Cytel Corporation and is related to the two U.S. patents noted below. A representative compound of the type described is the peptide of Formula (0.0.2):
N-Phenylacetyl-Leu-Asp-Phe-NCy3xe2x80x83xe2x80x83(0.0.2) 
wherein NCy3 is selected from, inter alia, morpholinamido; thiomorpholinamido; 4-(thiadioxo)piperidinamido; and D-2-(carboxamide)-pyrrolidinamido; piperidinamido; and substituted piperidinamido.
WO 95/15973 . . . U.S. Pat. No. 5,821,231 . . . U.S. Pat. No. 5,936,065 . . . Cytel Corporation
Further work by Arrhenius et al. involving cyclic CS-1 peptidomimetics is described in WO 96/06108 assigned to the Cytel Corporation, which is related to the U.S. patent noted below.
WO 96/06108 . . . U.S. Pat. No. 5,869,448 . . . Cytel Corporation
The Arrhenius group has also discovered non-peptidal inhibitors of VLA-4 dependent cell binding as described in He et al., WO 98/42656. The inhibitors therein described are of the general Formula (0.0.3): 
A typical inhibitor is that represented by Formula (0.0.4): 
WO 98/42656 . . . Cytel Corporation
The Leu-Asp-Val tripeptide has been used as the core of a group of inhibitors of VLA-4 dependent cell adhesion described in Adams et al. WO 96/22966, which is assigned to Biogen, Inc. These inhibitors may be represented by Formula (0.0.5): 
where R1 may be 4-(Nxe2x80x2-(2-methylphenyl)urea)phenylmethyl; Y may be Cxe2x95x90O; R2 may be H; R3 may be iso-butyl; and R14 may be 1,3-benzodioxol-5-yl. An example of a typical inhibitor of this type is that of Formula (0.0.6): 
WO 96/22966 . . . Biogen, Inc.
The Adams group has also discovered semi-peptidic cell adhesion inhibitors for the treatment of inflammation and autoimmune disease, described in Lin et al., WO 97/03094. These inhibitors may be represented by Formula (0.0.7):
Z-(Y1)-(Y2)-(Y3)n-Xxe2x80x83xe2x80x83(0.0.7) 
where Z may be 4-(Nxe2x80x2-(2-methylphenyl)urea)phenylacetyl; (Y1)-(Y2)-(Y3)n represents a series of amino acids forming a peptide chain; and X may be OH. A typical inhibitor of this type is shown in Formula (0.0.8): 
WO 97/03094 . . . Biogen, Inc.
The Adams group has also asserted, in Zheng et al., WO 98/04247, the discovery that existing IIb/IIIa integrin inhibitory compounds may be converted into VLA-4 inhibitory compounds, and that IIb/IIIa inhibitory compounds can be made by combining a unique VLA-4 integrin scaffold with a IIIb/IIIa specificity determinant. These cell adhesion inhibitors may be viewed as comprising a compound of the formula: A-B, where A comprises a VLA-4 specificity determinant which does not impart significant IIb/IIIa integrin inhibitory activity, and B is an integrin scaffold derived from a IIb/IIIa inhibitor. A three dimensional pharmacophore model of a compound having VLA-4 inhibitory activity is also described. Representative of the inhibitors thus derived are the compounds of Formulas (0.0.9) and (0.0.10): 
WO 98/04247 . . . Biogen, Inc.
See also Singh et al., WO 98/04913, which refers to a three dimensional pharmacophore model of a compound having VLA-4 inhibitory activity, comprising features defined by a table of tolerances and three dimensional coordinates x, y, and z. The following compound, representative of those referred to, may be represented by Formula (0.0.11): 
WO 98/04913 . . . Biogen, Inc.
Another type of VLA-4 dependent cell adhesion inhibitor is that described in Head et al., xe2x80x9cAnti-inflammatory Tyrosine Derivativesxe2x80x9d, WO 98/54207, which may be represented by general Formula (0.0.12): 
where R1 is an optionally substituted alkyl or aromatic group; X2 is xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94C(xe2x95x90O)Oxe2x80x94; xe2x80x94C(xe2x95x90O)NHxe2x80x94; or xe2x80x94S(xe2x95x90O)2xe2x80x94; and R7 is an optionally substitutued alkyl or aryl group. A compound typical of this type of inhibitor may be represented by Formula (0.0.13): 
WO 98/54207 . . . Celltech Therapeutics Ltd.
The Head group has also discovered a related group of VLA-4 dependent cell adhesion inhibitors, described in Head et al., xe2x80x9cPhenylalanine Derivatives Useful As Pharmaceutical Agents,xe2x80x9d WO 99/37618, which are of the general Formula (0.0.14): 
where Lxe2x80x2 is a linker atom or group; A is a chain xe2x80x94[C(R7)(R8)]pxe2x80x94Yxe2x80x94[C(R9)(R10)]qxe2x80x94; and L2 is a linker group selected from xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94C(xe2x95x90O)Oxe2x80x94; xe2x80x94C(xe2x95x90S)xe2x80x94; xe2x80x94S(xe2x95x90O)2, or xe2x80x94C(xe2x95x90O)N(R11)xe2x80x94. An example of this type of inhibitor is that of a compound of Formula (0.0.15): 
WO 99/35163 . . . Celltech Therapeutics, Ltd.
Another closely related group of VLA-4 inhibitors discovered by the Head group is described in Head et al., xe2x80x9cNovel Phenylalanine Derivatives Useful as Integrin Antagonists,xe2x80x9d WO 99/37618, which is characterized by general Formula (0.0.16): 
A representative example of these inhibitory compounds is that of Formula (0.0.17): 
WO 99/37618 . . . Celltech Therapeutics, Ltd.
A still further related group of compounds discovered by the Head group to be inhibitors of VLA-4 dependent cell adhesion is described in Head et al., xe2x80x9cPhenylalanine Derivatives As Inhibitors of Alpha4 Integrins,xe2x80x9d WO 99/43642, and may be characterized by general Formula (0.0.18): 
Inhibitors of the type described are illustrated in Formula (0.0.19): 
WO 99/43642 . . . Celltech Therapeutics, Ltd.
Early work in the discovery of inhibitors of VLA-4 dependent cell adhesion has also been done by Pleiss and Thorsett and their co-workers, e.g., as described in Thorsett et al., xe2x80x9cInhibitors of Leukocyte Adhesion,xe2x80x9d WO 96/01544 assigned to Athena Neurosciences, Inc. These inhibitors comprise inhibitors that block cellular adhesion mediated by VLA-4 and they are used to treat a number of inflammatory diseases, especially inflammatory brain disorders.
Non-peptide, i.e., small molecule inhibitors of VLA-4 have also been discovered by the Pleiss and Thorsett group, e.g., as described in Thorsett, xe2x80x9cCarbamoyloxy Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4,xe2x80x9d WO 99/06390 assigned to Athena Neurosciences, Inc. Inhibitors of this type may be represented by general Formula (0.0.20): 
where R1 is alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl, all of which are optionally substituted; R2 is defined similarly to R1 and may be combined with it and the xe2x80x94S(xe2x95x90O)2-moiety to form an optionally substituted heterocyclic group; R3 is defined similarly to R1 and is optionally taken together with the nitrogen atom bound to R2 and the carbon atom bound to R3 to form an optionally substituted heterocyclic group; R7 is xe2x80x94H or alkyl; Ar is optionally substituted aryl or heteroaryl; and R5 is xe2x80x94Oxe2x80x94Zxe2x80x94NR8R8xe2x80x2 or xe2x80x94Oxe2x80x94Zxe2x80x94R12 where Z is xe2x80x94C(xe2x95x90O) or xe2x80x94S(xe2x95x90O)2, R8 and R8xe2x80x2 are xe2x80x94H, or optionally substituted alkyl, cycloalkyl or hetercyclic, or R8 and R8xe2x80x2 may be joined to form an optionally substituted heterocycle, and R12 is optionally substituted heterocycle.
A representative example of the above-described VLA-4 inhibitors is the compound of Formula (0.0.21): 
WO 99/06390 . . . Athena Neurosciences, Inc.
In Yednock and Pleiss xe2x80x9cAlpha-9 Integrin Antagonists and Anti-inflammatory Compositions thereof,xe2x80x9d WO 99/06391 assigned to Athena Neurosciences, Inc., there is described the use of the inhibitory compounds of above-mentioned WO 99/06390 in methods of treating disorders that involve binding of xcex1-9 integrin, particularly adhesion macrophages or neutrophils. Disorders said to be susceptible to treatment include airway hyper-responsiveness and occlusion that occur in conjunction with chronic asthma, smooth muscle cell proliferation in atherosclerosis, vascular occlusion following angioplasty, fibrosis and glomerular scarring as a result of renal disease, aortic stenosis, hypertrophy of synovial membranes in rheumatoid arthritis, and inflammation and scarring that occur with the progression of ulcerative colitis, and Crohn""s disease.
The Thorsett and Pleiss group has discovered a group of inhibitors of VLA-4 which is described in Thorsett et al. xe2x80x9cSubstituted Phenylalanine Type Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4,xe2x80x9d WO 99/06431 assigned to Athena Neurosciences, Inc. and American Home Products Corporation, which may be represented by general Formula (0.0.22): 
where R1, R2, R3, R7, and Ar have substantially the same meaning as described above with respect to WO 99/06390; and R5 is an optionally substituted member selected from the group consisting of xe2x80x94NHC(xe2x95x90O)R; alkoxyaryl; aryl; heteroaryl; xe2x80x94NRRxe2x80x2; alkoxy-NRRxe2x80x2; alkenyl; alkynyl; aryloxy; heteroaryloxy; alkoxy-heterocyclic; O-heterocyclic; tetrazolyl; xe2x80x94NRS(xe2x95x90O)2-alkyl; alkenylsulfonylamino; alkynylsulfonylamino; alkoxy; amidine; xe2x80x94C(xe2x95x90O)NRRxe2x80x2; xe2x80x94NRC(xe2x95x90O)Rxe2x80x2; xe2x80x94S(xe2x95x90O)2-aryl; S(xe2x95x90O)2-heteroaryl; xe2x80x94NRC(xe2x95x90O)NRRxe2x80x2; xe2x80x94NRC(xe2x95x90O)ORxe2x80x2; aminocarbonyl-(N-formylheterocyclyl); and alkyl-C(xe2x95x90O)NH-heterocyclyl.
A compound which illustrates the type of VLA-4 inhibitors disclosed is that of Formula (0.0.23): 
WO 99/06431 . . . Athena Neurosciences, Inc.
A related group of inhibitory compounds which has also been discovered by the Thorsett and Pleiss group is described in Thorsett et al., xe2x80x9cDipeptide and Related Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4,xe2x80x9d WO 99/06432 assigned to Athena Neurosciences, Inc. and American Home Products Corporation. Inhibitory compounds of this type are characterized by general Formula (0.0.24): 
where R1, R2, R3, and R7 have substantially the same meaning as described above with respect to WO 99/06390 and WO 99/06431; and R5 is -ALK-X or xe2x95x90CHxe2x80x94Y where X and Y are defined to mean a wide variety of groups, all of which are optionally substituted.
An example of this type of VLA-4 inhibitor is the compound of Formula (0.0.25): 
WO 99/06432 . . . Athena Neurosciences, Inc.
A further related group of VLA-4 inhibitory compounds which has also been discovered by the Thorsett and Pleiss group is described in Dappen et al., xe2x80x9cCompounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4,xe2x80x9d WO 99/06433 assigned to Athena Neurosciences, Inc. and American Home Products Corporation. Inhibitory compounds of this type are characterized by general Formula (0.0.26): 
where R1, R2, R3, and R7 have substantially the same meaning as described above with respect to WO 99/06390, WO 99/06431, and WO 99/06432; and X is xe2x80x94H; xe2x80x94OH; acylamino; xe2x80x94C(xe2x95x90O)OH; and optionally substituted alkyl; alkoxy; aryl; aryloxy; aryloxyaryl; carboxy-alkyl; carboxy-cycloalkyl; carboxy-aryl; carboxy-heteroaryl; carboxy-heterocyclic; and cycloalkyl.
The type of VLA-4 inhibitor described in the paragraph immediately above may be represented by the compound of Formula (0.0.27): 
WO 99/06433 . . . Athena Neurosciences, Inc.
A still further group of VLA-4 inhibitory compounds which has been discovered by the Thorsett and Pleiss group is described in Ashwell et al., xe2x80x9c4-Amino-Phenylalanine Type Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4,xe2x80x9d WO 99/06434 assigned to Athena Neurosciences, Inc. and American Home Products Corporation. Inhibitory compounds of this type are characterized by general Formula (0.0.28): 
where R1, R2, R3, and R7 have substantially the same meaning as described above with respect to WO 99/06390, WO 99/06431, WO 99/06432, and WO 99/06433; and R is xe2x80x94H, alkyl, or aryl; X is O, S, or NR; and Y is NRRxe2x80x2 or heterocycle, all of which are optionally substituted by a wide variety of groups.
This further type of VLA-4 inhibitor may be illustrated by the compound of Formula (0.0.29): 
WO 99/06434 . . . Athena Neurosciences, Inc.
Another group of VLA-4 inhibitors structurally related to those groups of VLA-4 inhibitors described above, which has been discovered by the Thorsett and Pleiss group is described in Thorsett et al., xe2x80x9cDipeptide Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4,xe2x80x9d WO 99/06435 assigned to Athena Neurosciences, Inc. and American Home Products Corporation. Inhibitory compounds of this type are characterized by general Formula (0.0.30): 
where R1, R2, R3, and R7 have substantially the same meaning as described above with respect to WO 99/06390, WO 99/06431, WO 99/06432, WO 99/06433, and WO 99/06434; R5 has substantially the same meaning as described above with respect to WO 99/06432; and R4 is xe2x80x94H; and optionally substituted alkyl; cycloalkyl; aryl; heteroaryl; heterocyclic; and R1 and R2 may be taken together, or R2 and R3 may be taken together, or R3 and R4 may be taken together to form cycloalkyl or heterocyclic groups.
This type of VLA-4 inhibitor may be illustrated by the compound of Formula (0.0.31): 
WO 99/06435 . . . Athena Neurosciences, Inc.
A still further group of structurally related inhibitors of VLA-4 dependent cell adhesion which has been discovered by the Thorsett and Pleiss group is described in Thorsett et al., xe2x80x9cBenzyl Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4,xe2x80x9d WO 99/06436 assigned to Athena Neurosciences, Inc. and American Home Products Corporation. Inhibitory compounds of this type are characterized by general Formula (0.0.32): 
where R1, R2, R3, and R7 have substantially the same meaning as described above with respect to WO 99/06390, WO 99/06431, WO 99/06432, WO 99/06433, and WO 99/06434; and Ar is aryl or heteroaryl. This type of VLA-4 inhibitor may be illustrated by the compound of Formula (0.0.33): 
WO 99/06436 . . . Athena Neurosciences, Inc.
There is a further description of compounds related structurally to those described above in WO 99/06390, WO 99/06431, WO 99/06432, WO 99/06433, WO 99/06434, WO 99/06435, and WO 99/06436, but distinguished from them by means of extensive provisos, that is set out in Thorsett et al., xe2x80x9cSulfonylated Dipeptide Compounds Which Inhibit Leukocyte Adhesion Mediated by VLA-4,xe2x80x9d WO 99/06437. Three such inhibitory compounds are those of Formulas (0.0.34) through (0.0.36): 
WO 99/06437 . . . Athena Neurosciences, Inc.
The Stilz and Wehner group has discovered a different class of compounds which possess inhibitory activity with regard to VLA-4 mediated cell adhesion. These inhibitory compounds are described, e.g., in Stilz et al., xe2x80x9c5-Ring Heterocycles As Inhibitors of Leukocyte Adhesion and As VLA-4 Antagonists,xe2x80x9d EP 842 943 assigned to Hoechst AG., which may be characterized by general Formula (0.0.37): 
where R is 4-amido-phenyl, 4-guanidino-phenyl, 4-aminomethyl-phenyl, 3-amino-propyl, or 3-guanidino-propyl; R1 is methyl or benzyl; R2 is xe2x80x94H, methyl, ethyl, optionally substituted benzyl, or naphthylmethyl; R3 is a mono-, di-, or tri-peptide; R4 is xe2x80x94H, methyl, or butyl; and R5 is xe2x80x94H, alkyl, cycloalkyl, or optionally substituted aryl. A representative compound falling within the scope of the above-described class of VLA-4 inhibitors is that of Formula (0.0.38): 
EP 842 943 . . . Hoechst AG.
The Stilz and Wehner group has also discovered inhibitory compounds which are structurally close to those in above-described EP 842 943, and which are described in Stilz et al., xe2x80x9cHeterocycles As Inhibitors of Leukocyte Adhesion and As Antagonists of VLA-4,xe2x80x9d EP 842 944. These compounds may be characterized by general Formula (0.0.39): 
where R4 is methyl or 4-R3-phenyl where R3 is 4,5-dihydroimidazol-2-yl or xe2x80x94C(xe2x95x90O)NH2; R2 is optionally substituted phenyl, pyridyl, or naphthyl; and R4 is xe2x80x94H, ethyl, n-butyl, or iso-butyl. A representative example of this type of inhibitory compound is that of Formula (0.0.40): 
EP 842 944 . . . Hoechst AG.
Further inhibitory compounds structurally close to those in above-described EP 842 944 are described in Stilz et al., EP 842 945, which may be characterized by general Formula (0.0.41): 
where R is 4-R -phenyl where R2 is xe2x80x94CN, xe2x80x94NO2, optionally substituted xe2x80x94NH2C(xe2x95x90O)NH, or xe2x80x94NH2C(xe2x95x90O)NHCH2; and R2 is optionally substituted phenyl. A representative example of this type of inhibitory compound is that of Formula (0.0.42): 
EP 842 945 . . . Hoechst AG.
The Stilz and Wehner group has also further discovered inhibitors of VLA-4 dependent cell adhesion which are described in Wehner et al., xe2x80x9cImidazolidine Derivatives with VLA-4 Antagonist Activity Useful for the Treatment of Diseases Mediated by Leukocyte Adhesion,xe2x80x9d EP 903 353 assigned to Hoechst Marion Roussel Deutschland GmBH. Compounds of this type are characterized by general Formula (0.0.43): 
where A is optionally substituted alkylene, alkenylene, phenylene, -phenyl-alkylene, or alkylene-phenyl-; L and M are a bond or xe2x80x94CH2xe2x80x94; X is optionally substituted xe2x80x94CH(R7)xe2x80x94 or xe2x80x94C(xe2x95x90CHR7)xe2x80x94 where R7 is optionally substituted alkyl, phenyl, furyl, thienyl, pyrrolyl, indazolyl, or pyridinyl; R1 is xe2x80x94H, cycloalkyl, optionally substituted alkyl, aryl, heterocyclyl; xe2x80x94C(xe2x95x90O)R6, or xe2x80x94SO2R where R6 is xe2x80x94H, cycloalkyl, optionally substituted alkyl, aryl, or heterocyclyl; R2 is xe2x80x94NH2, xe2x80x94C(xe2x95x90O)NH2, or xe2x80x94C(xe2x95x90O)OH; R3 is xe2x80x94H, alkyl, optionally substituted aryl, or heterocyclyl; and R5 is xe2x80x94C(xe2x95x90O)OH, tetrazolyl, xe2x80x94SO3H, or xe2x80x94SO2NH2.
A typical VLA-4 inhibitor falling within the above-described class of compounds is illustrated by Formula (0.0.44): 
EP 903 353 . . . Hoechst Marion Roussel Deutschland GmBH
Another group of inhibitory compounds closely related in structure to those above-described has been discovered by the Stilz and Wehner group and is described in Wehner et al., xe2x80x9cSubstituted Imidazoline Derivatives with VLA-4 Antagonist Activity,xe2x80x9d EP 918 059. Said group may be illustrated by general Formula (0.0.45): 
where R is methyl or phenyl; R1 is tert-butyl, propyl, iso-propyl, benzyl, cyclohexyl, or optionally substituted phenyl; R3 is adamantyl, xe2x80x94CH(CH3)CH2C(xe2x95x90O)OH, optionally substituted xe2x80x94CH(phenyl)CH2C(xe2x95x90O)OH or xe2x80x94CH(phenyl)C(xe2x95x90O)OH; and R4 is xe2x80x94H or iso-butyl. An example of a compound which illustrates this class of VLA-4 inhibitors is that of Formula (0.0.46): 
EP 918 059 . . . Hoechst Marion Roussel Deutschland GmBH
Yet another class of VLA-4 inhibitors has been discovered by the Chen group, e.g., as described in Chen et al., xe2x80x9cNovel N-Aroylphenylalanine Derivatives As Integrin Antagonists,xe2x80x9d WO 99/10312 assigned to F. Hoffmann-La Roche AG. This class of inhibitors may be illustrated by general Formulas (0.0.47) and (0.0.48): 
where there are two sub-classes of compounds based on different A rings as shown above. Further, the A and B rings may be replaced with various heterocycles, although an ortho-substituted B ring is preferred. A representative example of a compound falling within this class of inhibitors is that of Formula (0.0.49): 
WO 99/10312 . . . F. Hoffmann-La Roche AG.
A closely related group of inhibitors discovered by the Chen group is described in Chen et al., WO 99/10313 assigned to F. Hoffmann-La Roche AG., which may be illustrated by general Formulas (0.0.50) and (0.0.51): 
where there are two sub-classes of compounds as described above in the case of those of Formulas (0.0.47) and (0.0.48). Further, the three R groups attached to the amide linker combine to form a quaternary center. A typical compound representative of the VLA-4 inhibitors in this class is that of Formula (0.0.52): 
WO 99/10313 . . . F. Hoffmann-La Roche AG.
A still further class of inhibitors of VLA-4 dependent cell adhesion is that discovered by Hagmann and his co-workers, e.g., as described in Durette and Hagmann, xe2x80x9cHeterocyclic Amide Compounds As Cell Adhesion Inhibitors,xe2x80x9d WO 98/53814 which is assigned to Merck and Co., Inc. This class of compounds may be illustrated by general Formula (0.0.53): 
where X is xe2x80x94C(xe2x95x90O)OH or acid isostere; Y is xe2x80x94C(xe2x95x90O) or xe2x80x94S(xe2x95x90O)2; R1 through R8 are selected from a wide variety of well known substituents; and A, B, and Z are selected so as to afford heterocycles of different types and ring sizes. An example of an inhibitory compound which is representative of this class is that of Formula (0.0.54): 
WO 98/53814 . . . Merck and Co., Inc.
Another class of structurally related inhibitory compounds discovered by the Hagmann group is described in Durette et al., xe2x80x9cBiarylalkanoic Acids As Cell Adhesion Inhibitors,xe2x80x9d WO 98/53817 assigned to Merck and Co., Inc., which may be illustrated by general Formulas (0.0.55) and (0.0.56): 
where X, Y, and R1 through R7 have substantially the same meaning as defined above for Formula (0.0.53), except that R2 and R3 may be taken together with the atoms to which they are attached to form a ring of 4 to 7 members containing 0-2 additional heteroatoms selected from O, S, and N; and Rb is optionally substituted alkyl, alkenyl, alkynyl, arylalkyl, or heteroarylalkyl. A representative example of a compound falling within the scope of this class of VLA-4 inhibitors is that of Formula (0.0.57): 
WO 98/53817 . . . Merck and Co., Inc.
A further class of inhibitory compounds discovered by the Hagmann group and closely related in structure to those described immediately above, is disclosed in Durette et al., xe2x80x9cSulfonamides As Cell Adhesion Inhibitors,xe2x80x9d WO 98/53818 assigned to Merck and Co., Inc. These compounds may be illustrated by general Formulas (0.0.57) and (0.0.58): 
where Rb and R1 through R7 have the same meaning as defined above for Formulas (0.0.55) and (0.0.56). A representative inhibitory compound falling within the above-described class is that of Formula (0.0.59): 
WO 98/53818 . . . Merck and Co., Inc.
A still further class of VLA-4 inhibitory compounds related in structure to those described above has been discovered by the Hagmann group and is disclosed in Delaszlo, xe2x80x9cAzapeptide Acids As Cell Adhesion Inhibitors,xe2x80x9d WO 99/20272. This class of inhibitors may be illustrated by general Formula (0.0.60): 
where m and n are 0 to 2; and X, Y, and R1 through R6 have the same meaning as defined above for Formulas (0.0.55) and (0.0.56). Representative inhibitory compounds falling within the above-described class are those of Formulas (0.0.61) and (0.0.62): 
WO 99/20272 . . . Merck and Co., Inc.
Another class of VLA-4 dependent cell adhesion inhibitors discovered by the Hagmann group is described in Delaszlo and Hagmann, xe2x80x9c4-Substituted-4-Piperidine Carboxamide Derivatives Useful in the Treatment of Asthma, Inflammation and Multiple Sclerosis.xe2x80x9d WO 99/25685 assigned to Merck and Co., Inc. Compounds of this class may be illustrated by general Formula (0.0.63): 
where X is a bond or substituted carbon atom; Z is xe2x80x94C(xe2x95x90O)OH or acid isostere; L is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94; and R1 through R5 have the substantially the same meaning as defined above for Formulas (0.0.55) and (0.0.56). A typical VLA-4 inhibitory compound in this class is that of Formula (0.0.64): 
WO 99/25685 . . . Merck and Co., Inc.
Another class of VLA-4 inhibitors closely related in structure to those described above is disclosed in Chang et al., xe2x80x9cCyclic Amino Acids As Cell Adhesion Inhibitors,xe2x80x9d WO 99/26615 assigned to Merck and Co., Inc. Inhibitory compounds of this class are illustrated by general Formula (0.0.65): 
where R indicates the ring size, and X, Y, and R1 through R7 have the same meaning as defined above for Formulas (0.0.55) and (0.0.56). A representative example of an inhibitory compound within this class is that of Formula (0.0.66): 
WO 99/26615 . . . Merck and Co., Inc.
A class of VLA-4 dependent cell adhesion inhibitors has been discovered which differs from those disclosed in WO 98/53814 described above only with respect to the terminal amino acid, which is a xcex2-amino acid. Accordingly, reference may be made to general Formula (0.0.53) above. These xcex2-amino acids are disclosed in Durette et al., xe2x80x9cSubstituted xcex2-Alanine Derivatives As Cell Adhesion Inhibitors,xe2x80x9d WO 99/26921 assigned to Merck and Co., Inc. Typical inhibitors of this type are illustrated in Formulas (0.0.67) and (0.0.68): 
WO 99/26921 . . . Merck and Co., Inc.
A further class of VLA-4 dependent cell adhesion inhibitors related in structure to those described above has been discovered by the Hagmann group and is disclosed in Chang et al., xe2x80x9cSubstituted Pyrrole Derivates As Cell Adhesion Inhibitors,xe2x80x9d WO 99/26922 assigned to Merck and Co., Inc. This class of inhibitors is illustrated by general Formula (0.0.69): 
where Y and R1 through R7 have the same meaning as defined above for Formulas (0.0.55) and (0.0.56), and X and Z have the same meaning as defined above for Formula (0.0.63), except that the meanings are reversed because -X-Z- in (0.0.63) has been changed to -Z-X- in (0.0.69). An example of inhibitory compounds falling within this class is illustrated by Formula (0.0.70): 
WO 99/26922 . . . Merck and Co., Inc.
Another class of VLA-4 inhibitory compounds discovered by the Hagmann group and closely related to those above is that described in Delaszlo and Hagmann, xe2x80x9cPara-Aminomethylaryl Carboxamide Derivatives,xe2x80x9d WO 99/26923 assigned to Merck and Co., Inc., and which may be represent by general Formula (0.0.71): 
where L, X, Z, and R1 through R6 have substantially the same meaning as defined above under Formulas (0.0.55) and (0.0.56). Ar is a 1,4 substituted aryl or heteroaryl moiety. A typical compound falling within the scope of this class of VLA-4 inhibitors is illustrated as Formula (0.0.72): 
WO 99/26923 . . . Merck and Co., Inc.
A different group has discovered a new class of VLA-4 antagonists which is described in Wattanasin and Von Matt, xe2x80x9cVLA-4 Antagonists,xe2x80x9d WO 99/37605 assigned to Novartis. The inhibitory compounds in this new class may be represented by general Formula (0.0.73): 
where Y is xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)2xe2x80x94, or xe2x80x94P(xe2x95x90O)2xe2x80x94; Z is xe2x80x94(CH2)nxe2x80x94, xe2x80x94CHRxe2x80x94, or xe2x80x94NRxe2x80x94; W is xe2x80x94CHxe2x80x94 or xe2x80x94Nxe2x80x94; X is xe2x80x94C(xe2x95x90O)OH or acid isostere; and R1 through R4 are a wide variety of common substituents. A representative example of a VLA-4 inhibitor from this class is illustrated by Formula (0.0.74): 
WO 99/37605 . . . Novartis
Another different group has discovered a further new class of compounds which inhibit VLA-4 dependent cell adhesion, which is described in Astles et al., xe2x80x9cSubstituted Anilides and Their Use in the Treatment of Various Disease States including Inflammation, arthritis, and atherosclerosis,xe2x80x9d WO 99/23063 assigned to Rhone-Poulenc Rorer Ltd. This class of VLA-4 inhibitors may be represented by general Formula (0.0.75): 
where X1, X2, and X3 are xe2x80x94Nxe2x80x94 or xe2x80x94CRxe2x80x94; Ar1 is aryl or heteroaryl; L2 is an optionally substituted alkylene linkage; Y is carboxy, an acid bioisostere, or xe2x80x94C(xe2x95x90O)NRR; and R1 is xe2x80x94H, halo, xe2x80x94OH, lower alkyl or lower alkoxy. A representative example of an inhibitory compound which fits into this class is illustrated by Formula (0.0.76): 
WO 99/23063 . . . Rhone-Poulenc Rorer Ltd.
Another class of VLA-4 inhibitors which is closely related in structure to those described immediately above is described in Artles et al. xe2x80x9cBiaryl xcex2-Alanine Derivatives Useful As VLA-4 Antagonists,xe2x80x9d WO 99/33789 assigned to Rhone-Poulenc Rorer Ltd. Members of this class of inhibitors may be represented by general Formula (0.0.77): 
where X1, X2, and Y have the same meaning as defined above under Formula (0.0.75). R4 is aryl or heteroaryl or is optionally substituted alkyl, alkenyl or alkynyl. A representative example of an inhibitory compound within this class is illustrated by Formula (0.0.78): 
WO 99/33789 . . . Rhone-Poulenc Rorer Ltd.
A further different group has also discovered a new class of VLA-4 dependent cell adhesion inhibitors, which is described in Lobl et al. xe2x80x9cCyclic Peptide Inhibitors of xcex21 and xcex22 Integrin-Mediated Adhesion,xe2x80x9d WO 96/40781 assigned to Tanabe Seiyaku Co., Ltd. The inhibitors are cyclic peptides which contain a free acid.
WO 96/40781 . . . Tanabe Seiyaku Co., Ltd.
Another class of VLA-4 inhibitors discovered by the same group is described in Lobl et al. xe2x80x9cInhibitors of xcex11xcex24 Mediated Cell Adhesion,xe2x80x9d WO 98/58902 assigned to Tanabe Seiyaku Co., Ltd. and Pharmacia and Upjohn Company. Members of this further class of VLA-4 inhibitors may be represented by general Formula (0.0.79): 
where R1 is acid or amide; X is phenyl; and Z is amide or methylene ether. A representative example of an inhibitory compound from this class is that of Formula (0.0.80): 
WO 98/58902 . . . Tanabe Seiyaku Co., Ltd.
Another class of VLA-4 inhibitors discovered by the same group is described in Sircar et al. xe2x80x9cInhibitors of xcex14 Mediated Cell Adhesion,xe2x80x9d WO 99/36393 assigned to Tanabe Seiyaku Co., Ltd. Members of this class of VLA-4 inhibitors may be characterized by general Formula (0.0.81): 
where R1 through R6, except R4, are selected from a wide variety of common substituent groups; R4 is acid, acid isostere, or amide; A is aryl or heteroaryl; Q is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, or substituted alkylene; n is 0 to 2; and W is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94Nxe2x95x90CHxe2x80x94. A representative member of this class of VLA-4 inhibitors is illustrated by Formula (0.0.82): 
WO 99/36393 . . . Tanabe Seiyaku Co., Ltd.
A still further different group has also discovered a new class of VLA-4 dependent cell adhesion inhibitors, which is described in Kogan et al. xe2x80x9cProcess to Inhibit Binding of the Integrin alpha 4 beta 1 to VCAM-1 or Fibronectin,xe2x80x9d WO 96/00581 assigned to Texas Biotechnology Corporation. This class of VLA-4 antagonists comprises cyclic peptides of from 5 to 13 residues modeled after a portion of the CS1 peptide, that also contain a free acid.
WO 96/00581 . . . Texas Biotechnology Corporation
A yet still further different group has also discovered a new class of VLA-4 antagonists, which is described in Dutta, xe2x80x9cFibronectin Adhesion Inhibitors,xe2x80x9d WO 96/20216 assigned to Zeneca Limited. This class of VLA-4 antagonists comprises cyclic peptides that contain a free acid.
WO 96/00581 . . . Zeneca Limited
A related class of VLA-4 antagonists discovered by the same group is described in Dutta, xe2x80x9cCyclic Tetrapeptide Dimers Useful As Fibronectin Inhibitors,xe2x80x9d WO 97/02289 assigned to Zeneca Limited. This class of VLA-4 antagonists comprises cyclic dimeric peptides in which a peptide 1 and peptide 2 independently representing a tetrapeptide, are juxtaposed in parallel or antiparallel orientation by means of two linking moieties L1 and L2.
WO 97/02289 . . . Zeneca Limited
Another related class of VLA-4 antagonists discovered by the same group is described in Dutta, xe2x80x9cCyclic Octapeptide Derivatives That Are Integrin Antagonists,xe2x80x9d WO 97/49731 assigned to Zeneca Limited. This class of VLA-4 antagonists comprises a variety of cyclic octapeptides containing a free acid.
WO 97/49731 . . . Zeneca Limited
The same group has also discovered a non-peptidal class of VLA-4 antagonists which is described in Brittain and Johnstone, xe2x80x9cChemical Compounds,xe2x80x9d WO 99/24398 assigned to Zeneca Limited. Members of this class may be represented by general Formula (0.0.83): 
where Y is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, or xe2x80x94S(xe2x95x90O)2xe2x80x94; R1 is urea; R11 is acid or acid isostere; and m is 0 or 1 and when m is 0 then n is 1 to 4, and when m is 1 then n is 0. A representative member of this class of VLA-4 antagonists is illustrated by Formula(0.0.84): 
WO 99/24398 . . . Zeneca Limited
None of the references discussed above discloses or suggests the compounds of the present invention.
Despite the above-described advances in the art with regard to inhibitors of VLA-4 mediated cell adhesion, the artisan will quickly recognize that the peptidyl inhibitors are prone to poor absorption, poor solubility and are subject to metabolism in vivo (both systemically and locally when administered directly into the lung) diminishing their opportunity to appreciably affect the course of an inflammatory, respiratory or autoimmune disease.
Those of the above-described VLA-4 antagonists that are non-peptidal, i.e., that may be regarded as small molecules, are thereby able to avoid the liabilities of peptidal agents as discussed above. However, the small molecule VLA-4 antagonists known in the art, as described in detail above, have not yet been established to possess sufficiently high levels of the desired potency with low levels of acceptable side effects, together with adequately workable pharmacokinetic and adsorption profiles, such as would enable such compounds to become suitable therapeutic agents for use in treating the diseases and conditions discussed herein. Accordingly, there still exists in the art a need for non-peptidyl or semi-peptidyl therapeutic agents which can effectively treat or prevent such pathological conditions.
The present invention is concerned with compositions which inhibit VLA-4 dependent cell adhesion in a mammal. The present invention thus relates to a compound of Formula (1.0.0): 
and pharmaceutically acceptable salts and other prodrug derivatives thereof, wherein:
A is (C1-C6) alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl as defined herein; where said alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with 0 to 3 R9; or is a member selected from the group consisiting of the following radicals: A1-NHC(xe2x95x90O)NH-A2-, A1-NHC(xe2x95x90O)O-A2-, A1-OC(xe2x95x90O)NH-A2-, A1-NHSO2NH-A2-, A1-NHC(xe2x95x90O)-A2-, A1-C(xe2x95x90O)NH-A2-, A1-NHSO2-A2-, A1-SO2NH-A2-, A1-(CH2)rO-A2-, A1-O(CH2)r-A2-, A1-(CH2)r-A2-, where A1 and A2 are each independently selected from the group consisting of hydrogen, aryl, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, cycloalkyl, heteroaryl, and heterocyclyl; where said aryl, alkyl, cycloalkyl, heteroaryl, or heterocyclyl group is substituted with 0 to 3 R9;
B is a member independently selected from the group consisting of the following: 
xe2x80x83where the symbol xe2x80x9c*xe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.1.0) through (1.1.22) to the moiety xe2x80x9cCR2R3xe2x80x9d in Formula (1.0.0); and
the symbol xe2x80x9cΠxe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.1.0) through (1.1.22) to the moiety xe2x80x9cExe2x80x9d in Formula (1.0.0); Each of Formula (1.1.0) through (1.1.22), with the exception of formulas (1.1.10) and (1.1.22), may be optionally substituted with R9;
E is a single bond; xe2x80x94Oxe2x80x94; xe2x80x94NR10xe2x80x94; xe2x80x94CHxe2x95x90CHxe2x80x94; xe2x80x94CCxe2x80x94; xe2x80x94S(xe2x95x90O)q; xe2x80x94CR11R12NR10xe2x80x94; or xe2x80x94CR11R12xe2x80x94;
X is xe2x80x94Oxe2x80x94; xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94(xe2x95x90O)q; or xe2x80x94NR10xe2x80x94;
X1, X2 and X3 are each independently selected from the group consisting of CH, CR9 or N;
Y is a single bond; xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94C(xe2x95x90S)xe2x80x94; or xe2x80x94S(xe2x95x90O)2xe2x80x94;
k is an integer independently selected from 0, 1 and 2;
m is an integer independently selected from 0 and 1;
n is an integer independently selected from 0, land 2;
p is an integer independently selected from 0 and 1, provided that p must be selected as 1 where B is selected as partial formula (1.1.0) through (1.1.11);
q is an integer independently selected from 0,1 and 2;
r is an integer independently selected from 0, 1 and 2;
R2 and R3 are each independently selected from the group consisting of hydrogen; (C1-C6) alkyl substituted with 0 to 3 R13; (C2-C6) alkenyl substituted with 0 to 3 R13; (C3-C14) carbocyclic ring system substituted with 0 to 3 R13; a heterocyclyl ring as defined herein, substituted with 0 to 3 R13; (C1-C6) alkyl-OR5 substituted with 0 to 3 R13; C1-C6) alkyl-SR5 substituted with 0 to 3 R13; (C1-C6) alkyl-SO2R5 substituted with 0 to 3 R13; a heteroaryl ring as defined herein, substituted with 0 to 3 R13; an aryl ring as defined herein, substituted with 0 to 3 R13;
xe2x80x83provided that
xe2x80x83R2 and R3 are each defined as above; or they are taken together as defined below; or one of them is taken together with R4 as defined below, in which case the other has the meaning of hydrogen or methyl;
R2 and R3 are taken together to form either a cycloalkyl or heterocyclyl ring substituted with 0 to 3 R13; or
R2 or R3 is taken together with R4 and the carbon and nitrogen atoms to which they are respectively attached to form a heteroaryl or heterocyclyl group as defined herein, substituted with 0 to 3 R13;
R4 is hydrogen; or (C1-C6) alkyl optionally substituted with R13; or R4 may be taken together with either R2 or R3 to form a carbocyclic or heterocyclic ring;
R5 and R6 are independently hydrogen; (C1-C6) alkyl; (C2-C6) alkenyl; (C2-C6) alkynyl; CF3; aryl; cycloalkyl; heteroaryl; or heterocyclyl;
R7 is (C1-C6) alkyl; (CH2)kOR5; (CH2)kNR6C(xe2x95x90O)R5; (CH2)kNR6C(xe2x95x90O)OR5; (CH2)kNR6SO2R5; (CH2)kNR6R5; F; CF3; OCF3; aryl, substituted with 0 to 3 R9; heterocyclyl, substituted with 0 to 3 R9; heteroaryl, substituted with 0 to 3 R9; cycloalkyl, substituted with 0 to 3 R9; or R7 may be taken together with R8 to form a cycloalkyl or heterocyclyl ring; or R7 may be taken together with R11 to form a cycloalkyl or heterocyclyl ring;
R8 is hydrogen; F; (C1-C6) alkyl or (C1-C6) alkoxy;
R9 is halogen; (C1-C6) alkyl; C1-C6) alkoxy; (C3-C6) cycloalkyl; (C3-C6) cycloalkoxy; cyano; (CH2)kOH; C(xe2x95x90O)R5; (CH2)kC(O)NR5R6; (CH2)kNR5R6; (CH2)kNR5SO2R6; CF3; OCF3; SO2NR5R6; (CH2)mC(xe2x95x90O)OR5; when R9 is attached to a saturated carbon atom R9 may be xe2x95x90O or xe2x95x90S; when R9 is attached to a sulphur atom R9 may be xe2x95x90O;
R10 is hydrogen; C(xe2x95x90O)R5; C(xe2x95x90O)OR5; (C1-C6) alkyl; aryl; heterocyclyl; heteroaryl; cycloalkyl; or SO2R5;
R11 and R12 are independently hydrogen; (C1-C6) alkyl; hydroxy; cyano; (C1-C6) alkoxy; NR6C(xe2x95x90O)R5; NR6SO2R5; NR6R5; CF3; F; aryl; heterocyclyl; heteroaryl; cycloalkyl; cycloalkoxy; or R11 may be taken together with R12 to form a cycloalkyl or heterocyclyl ring;
R13 is independently selected from the group consisting of halogen; CF3; (C1-C6) alkyl; aryl; heteroaryl; heterocyclyl; hydroxy; cyano; (C1-C6) alkoxy; (C3-C6) cycloalkyl; (C3-C6) cycloalkoxy; (C2-C6) alkynyl; (C2-C6) alkenyl; xe2x80x94NR6R5; xe2x80x94C(xe2x95x90O)NR5R6; SO2R5; C(xe2x95x90O)R5; NR5SO2R6; NR5C(xe2x95x90O)R6; C(xe2x95x90O)NR5SO2R6; NR5C(xe2x95x90O)OR6; and SO2NR6R5.
The present invention is also concerned with pharmaceutical compositions comprising one or more of the compounds of the present invention as described above together with a pharmaceutically acceptable carrier for said compound(s), wherein the amount of said compound(s) present is effective for preventing, inhibiting, suppressing or reducing cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4. The present invention is further concerned with pharmaceutical compositions which in addition to containing a compound of the present invention, additionally comprise one or more therapeutic agents selected from the group consisting essentially of anti-inflammatory corticosteroids, nonsteroidal anti-inflammatory agents, bronchodilators, anti-asthmatic agents, and immunosuppressant agents.
The present invention is still further concerned with a method of treating or preventing an inflammatory, autoimmune or respiratory diseases by inhibiting cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a pharmaceutical composition of the present invention. The pharmaceutical compositions of the present invention may be used in the treatment of many inflammatory, autoimmune and respiratory diseases, including but not limited to asthma, multiple sclerosis, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, psoriasis, host rejection following organ transplantation, atherosclerosis, and other diseases mediated by or associated with VLA-4.
The present invention relates to compounds which inhibit cell adhesion and subsequent pathogenic processes mediated by VLA-4. These compounds, which are thus useful in the treatment of many inflammatory, autoimmune amd respiratory diseases, may be illustrated by Formula (1.0.0): 
For compounds of Formula (1.0.0), the terminal group identified as A has the meaning alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl substituted with 0 to 3 R9; or is a member selected from the group consisiting of the following radicals: A1-NHC(xe2x95x90O)NH-A2-, A1-NHC(xe2x95x90O)O-A2-, A1-OC(xe2x95x90O)NH-A2-, A1-NHSO2NH-A2-, A1-NHC(xe2x95x90O)-A2-, A1-C(xe2x95x90O)NH-A2-, A1-NHSO2-A2-, A1-SO2NH-A2-, A1-(CH2)rO-A2-, A1O(CH2)r-A2-, A1(CH2)r-A2-, where A1 and A2 is each independently selected from the group consisting of hydrogen, aryl, alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, and heterocyclyl; where said aryl, alkyl, alkenyl, cycloalkyl, heteroaryl, or heterocyclyl group is substituted with 0 to 3 R9.
The term xe2x80x9calkylxe2x80x9d as used with reference to xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, and whether used alone or in combination, refers to a straight-chain or branched chain alkyl radical containing the indicated number of carbon atoms, usually from 1 to 6 but often from 1 to 4, carbon atoms. Examples of such radicals include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl, iso-amyl, and hexyl.
The term xe2x80x9ccycloalkylxe2x80x9d as used with reference to xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, and whether used alone or in combination, refers to a cyclic alkyl radical containing from 3 to 6 carbon atoms. Examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term xe2x80x9carylxe2x80x9d as used with reference to xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, is intended to refer to a carbocyclic aromatic group which is a member selected from the group consisting essentially of phenyl, naphthyl, indenyl, indanyl, and fluorenyl. It is preferred, however, that where xe2x80x9cAxe2x80x9d is xe2x80x9carylxe2x80x9d, that it is phenyl.
The term xe2x80x9cheteroarylxe2x80x9d as used with reference to xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, is intended to refer to a heterocyclic aromatic group which is a member selected from the group consisting essentially of furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, pyranyl, parathiazinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, 2,3-dihydrobenzofuranyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and pyrazolo[1,5-c]triazinyl.
It is preferred, however, that where xe2x80x9cAxe2x80x9d is xe2x80x9cheteroarylxe2x80x9d that it is furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridyl, pyrimidinyl, indolyl, benzo[b]furanyl, benzimidazolyl, or quinolinyl. More preferably, xe2x80x9cAxe2x80x9d is pyridyl.
The terms xe2x80x9cheterocylicxe2x80x9d and xe2x80x9cheterocyclylxe2x80x9d as used with reference to xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, are both intended to refer to a non-aromatic 3- to 10-membered carbocyclic ring in which at least one of the carbon atoms of the ring has been replaced by a heteroatom selected from N, O or S. Preferably two, and more preferably one heteroatom is present, except that in the case of nitrogen, as many as four N heteroatoms may be present. The heterocyclyl group may comprise one or two fused rings, and further may include an aryl-fused ring. In a preferred meaning, xe2x80x9cheterocyclylxe2x80x9d refers to a member selected from the group consisting essentially of oxiranyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and benzodioxolane, especially 1,3-benzodioxol-5-yl.
It is preferred, however, that where xe2x80x9cAxe2x80x9d is xe2x80x9cheterocyclylxe2x80x9d that it is pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl.
Where xe2x80x9cAxe2x80x9d is defined as a moiety selected from the above-defined alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl groups, said moiety may be substituted with 0 to 3 R9. The choice of xe2x80x9c0xe2x80x9d merely denotes that there are no substituents, substitution being optional. Where substitution occurs, preferably there are two substituents, and more preferably there is only one substituent.
Where a substituent R9 is used, it will be independently selected from the group consisting essentially of halogen; (C1-C6) alkyl; C1-C6) alkoxy; (C3-C6) cycloalkyl; (C3-C6) cycloalkoxy; cyano; hydroxy; C(xe2x95x90O)R5; C(O)NR5R6; NR5R6; NR5SO2R6; CF3; OCF3; SO2NR5R6; C(xe2x95x90O)OR5; when R9 is attached to a saturated carbon atom R9 may be xe2x95x90O or xe2x95x90S; when R9 is attached to a sulphur atom R9 may be xe2x95x90O; where R5 and R6 are as further defined herein. Preferably, however, there is a single substituent and it is F, Cl, OH, methyl, methoxy, cyclohexyl, acetyl, cyclopropyloxy, or F3Cxe2x80x94.
The term xe2x80x9calkoxyxe2x80x9d as used with reference to the substituents xe2x80x9cR9xe2x80x9d on the group xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, and whether used alone or in combination, refers to an alkyl ether radical, wherein the term xe2x80x9calkylxe2x80x9d is as defined above. Examples of suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy.
The term xe2x80x9ccycloalkoxyxe2x80x9d as used with reference to the substituents xe2x80x9cR9xe2x80x9d on the group xe2x80x9cAxe2x80x9d, as well as in other contexts throughout the instant specification, and whether used alone or in combination, refers to an cycloalkyl ether radical, wherein the term xe2x80x9ccycloalkylxe2x80x9d is as defined above. Examples of suitable cycloalkoxy radicals include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.
A preferred meaning of xe2x80x9cAxe2x80x9d is that of a divalent radical which is a member selected from the group consisting of the following radicals: A1-NHC(xe2x95x90O)NH-A2-, A1-NHC(xe2x95x90O)O-A2-, A1-OC(xe2x95x90O)NH-A2-, A1-NHSO2NH-A2-, A1-NHC(xe2x95x90O)-A2-, A1-C(xe2x95x90O)NH-A2-, A1-NHSO2-A2-, A1-SO2NH-A2-, A1-(CH2)rO-A2-, A1-O (CH2)r-A2-, A1-(CH2)r-A2-, A1-(CH2)r-A2-, where A1 and A2 is each independently selected from the group consisting of hydrogen, aryl, (C1-C6) alkyl, cycloalkyl, heteroaryl, and heterocyclyl; where said aryl, alkyl, cycloalkyl, heteroaryl, or heterocyclyl group is substituted with 0 to 3 R9. The alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl group which is bonded to one or both sides of the ureido radical is selected in accordance with the definitions set out above, as are the 0 to 3 substituents R9. It is preferred that an aryl group be covalently bonded to the both sides of the ureido radical, and it is further preferred that this aryl group be phenyl. It is most preferred that said phenyl group have a single substituent which is preferably F, Cl, methyl, methoxy, or F3Cxe2x80x94. Examples of the preferred meanings of xe2x80x9cAxe2x80x9d are shown in partial Formulas (4.0.0) though (4.0.11): 
The component of the compounds of Formula (1.0.0) which is immediately adjacent to the xe2x80x9cAxe2x80x9d component, is a single bond, or a methylene or ethylene bridging element where n=0, 1 or 2, respectively. It is preferred that n=1 and that there be a methylene bridge. Accordingly, within the context of the above-stated preferences for the meaning of the xe2x80x9cAxe2x80x9d component, and adding the methylene bridge, the following most preferred termini which include the component xe2x80x9cAxe2x80x9d, may be represented by the following partial Formulas (4.1.0) through (4.1.23): 
It will be further noted partial structural formulas that the preferred methylene bridge is also preferably attached to the N,Nxe2x80x2-diphenylureido group in a para relationship to the point of attachment of the divalent ureido group to the phenyl group involved.
The xe2x80x9cYxe2x80x9d component of Formula (1.0.0) may be xe2x80x94C(xe2x95x90O)xe2x80x94; xe2x80x94C(xe2x95x90S)xe2x80x94; or xe2x80x94S(xe2x95x90O)2xe2x80x94. Overall, however, it is most preferred that xe2x80x9cYxe2x80x9d be a carbonyl moiety, i.e., that xe2x80x9cYxe2x80x9d is the moiety xe2x80x94C(xe2x95x90O)xe2x80x94.
The next component of the compounds of Formula (1.0.0) is xe2x80x94NR4CR2R3xe2x80x94. In this component R2 and R3 are each independently selected from the group consisting of hydrogen; (C1-C6) alkyl substituted with 0 to 3 R13; (C2-C6) alkenyl substituted with 0 to 3 R13; a (C3-C14) carbocyclic ring system substituted with 0 to 3 R13; a heterocyclyl ring as defined herein, substituted with 0 to 3 R13; (C1-C6) alkyl-OR5 substituted with 0 to 3 R13; (c1-C6) alkyl-SR5 substituted with 0 to 3 R13; (C1-C6) alkyl-SO2R5 substituted with 0 to 3 R13; a heteroaryl ring as defined herein, substituted with 0 to 3 R13; and an aryl ring as defined herein, substituted with 0 to 3 R13. R2 and R3 may also be taken together in accordance with an optional definition of R2 and R3, in which case they form a cycloalkyl or heterocyclyl ring substituted with 0 to 3 R3. For example, where R2 and R3 are taken together to form a spirocyclic cyclopropyl, cyclobutyl, or cyclopentyl group, the resulting compounds of the present invention will include moieties such as those of partial Formulas (1.2.0) through (1.2.2): 
Another preferred sub-group of compounds of the present invention is that formed when either R2 or R3 is taken together with R4 and the carbon and nitrogen atoms to which they are respectively attached to form a heteroaryl or heterocyclyl group as defined herein. Said heteroaryl or heterocyclycl group may, in turn, be substituted with 0 to 3 R13. In accordance with the above-mentioned proviso, when either R2 or R3 is taken together with R4, the other must be hydrogen or methyl. The sub-group may be represented by partial Formula (1.3.0) as follows: 
where the symbol xe2x80x9c*xe2x80x9d indicates the point of attachment of the moiety represented by partial Formula (1.3.0) to the moiety xe2x80x9cYxe2x80x9d in Formula (1.0.0); and the symbol xe2x80x9cΠxe2x80x9d indicates the point of attachment of the moiety represented by partial Formula (1.3.0) to xe2x80x9cBxe2x80x9d in Formula (1.0.0), defined by partial Formulas (1.1.0) through (1.1.22). The substituent xe2x80x9cR⅔xe2x80x9d indicates the presence of either the R2 substituent or the R3 substituent. They both may not be present, since one or the other has already been selected to be taken together with R4 to form the heteroaryl or heterocyclyl group of partial Formula (1.3.0), represented as follows: 
It will be understood that whether R2 or R3 is present, it will have the meaning of hydrogen, alkyl or methyl.
Accordingly, this sub-group of the group xe2x80x9cxe2x80x94NR4CR2R3Bxe2x80x94xe2x80x9d represented by partial Formula (1.3.0) includes, but is not limited to, the embodiments which are represented by partial Formulas (1.3.1) through (1.3.20): 
where the symbol xe2x80x9c*xe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.3.1) through (1.3.20) to the moiety xe2x80x9cYxe2x80x9d in Formula (1.0.0); and the symbol xe2x80x9cΠxe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.3.1) through (1.3.20) to the moiety xe2x80x9cExe2x80x9d in Formula (1.0.0).
With reference to the optional substituent R13 which may be present on the R2 and R3 substituents of the B component, R13 is absent when xe2x80x9c0xe2x80x9d is selected. It is preferred that R13 either be absent or be present as a single substituent selected from halogen; CF3; (C1-C6) alkyl; aryl; heteroaryl; heterocyclyl; hydroxy; cyano; (C1-C6) alkoxy; (C3-C14) carbocyclic ring system; (C3-C6) cycloalkoxy; (C2-C6) alkynyl; (C2-C6) alkenyl; xe2x80x94NR6R5; xe2x80x94C(xe2x95x90O)NR5R6; SO2R5; C(xe2x95x90O)R5; NR5SO2R6; NR5C(xe2x95x90O)R6; C(xe2x95x90O)NR5SO2R6; NR5C(xe2x95x90O)OR6; and SO2NR5. With reference to the optional substituent R13, but also with reference to the remainder of the instant specification, the term xe2x80x9calkynylxe2x80x9d alone or in combination, refers to a straight-chain or branched-chain alkynyl radical containing from 2 to 6, preferably 2 to 4 carbon atoms. Examples of such radicals include, but are not limited to, ethynyl (acetylenyl), propynyl, propargyl, butynyl, hexynyl, decynyl and the like.
With reference to the definition of R13, the term xe2x80x9calkenylxe2x80x9d alone or in combination, refers to a straight-chain or branched-chain alkenyl radical containing from 2 to 6, preferably 2 to 4 carbon atoms. Examples of such radicals include, but are not limited to, ethenyl, E- and Z-propenyl, iso-propenyl, E- and Z-butenyl, E- and Z-iso-butenyl, and E- and Z-pentenyl.
The term xe2x80x9c(C3-C14)carbocyclic ring systemxe2x80x9d as used with reference to R2 and R3, as well as in other contexts throughout the instant specification, used alone or in combination, is intended to refer to cycloalkyl and cycloalkenyl groups consisting of one, two or three fused rings containing a total of from three to fourteen carbon atoms. The term xe2x80x9ccycloalkylxe2x80x9d in turn, means a cyclic alkyl radical containing from 3 to 8, preferably from 3 to 6, carbon atoms. Examples of such cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term xe2x80x9ccycloalkenylxe2x80x9d on the other hand, refers to a cyclic carbocycle containing from 4 to 8, preferably 5 or 6, carbon atoms and one or more double bonds. Examples of such cycloalkenyl radicals include, but are not limited to, cyclopentenyl, cyclohexenyl, and cyclopentadienyl.
Where two or three fused rings are present, one of the rings may be a cycloalkyl ring system while the other one or two rings may be cycloalkenyl ring systems.
It is preferred that when one of R2 and R3 is hydrogen that the other be selected from the group consisting essentially of hydrogen, methyl, ethyl, propyl, butyl, and iso-butyl; hydroxymethyl, methoxymethyl; allyl, propenyl, E- and Z-iso-butenyl, and E- and Z-pentenyl; cyclopropylmethyl, cyclopentylmethyl and cyclohexylmethyl; cyclohexenylmethyl, benzyl, benzyloxymethyl and phenoxymethyl; 2-(methylthio)ethyl; 3-(hydroxypropylthio)methyl; 2-(methylsulfonyl)ethyl; 4-(acetylamino)butyl; 4-(methylsulfonylamino)butyl; and 4-ethoxycarbonylamino)butyl.
The next component, the xe2x80x9cBxe2x80x9d group of the compounds of Formula (1.0.0) is one of the more important portions of the molecule and is a key element in providing the unexpectedly good biological properties possessed by the compounds of the present invention. The xe2x80x9cBxe2x80x9d group comprises a member selected from the group consisting of partial Formulas (1.1.0) through (1.1.22): 
where the symbol xe2x80x9c*xe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.1.0) through (1.1.22) to the moiety xe2x80x9cCR2R3xe2x80x9d in Formula (1.0.0); and the symbol xe2x80x9cΠxe2x80x9d indicates the point of attachment of the moiety represented by each partial Formula (1.1.0) through (1.1.22) to the moiety xe2x80x9cExe2x80x9d in Formula (1.0.0).
All of the above partial Formulas (1.1.0) through (1.1.22) inclusive are illustrated as fragments in the manner above-described, wherein the points of attachment at either end of a particular fragment are indicated by the symbols xe2x80x9c*xe2x80x9d and xe2x80x9cΠxe2x80x9d.
In the above partial formulas defining the B component of the compounds of Formula (1.0.0), the moiety xe2x80x9cXxe2x80x9d may be oxygen; sulfur (q=0) and sulfur to which two oxygen atoms is attached (q=2), i.e., sulfonyl; or NH (R10=hydrogen) or nitrogen which is substituted (R10=(C1-C6)alkyl; (C3-C6)cycloalkyl; heterocyclyl; heteroaryl; or aryl). It is preferred, however, that xe2x80x9cXxe2x80x9d be simply oxygen, sulfur or NH.
Attached to component B in the compounds of Formula (1.0.0) are the remaining structural elements which may be represented by partial Formula (1.4.0): 
It will be noted first that the moiety represented by partial Formula (1.4.0) is directly attached to component B in the overall compound of Formula (1.0.0). E is a single bond; oxygen; xe2x80x94NR10xe2x80x94; xe2x80x94CHxe2x95x90CHxe2x80x94; or xe2x80x94CR11R12xe2x80x94.
Where a substituent R10 is used, it will be independently selected from the group consisting essentially of hydrogen, C(xe2x95x90O)R5; (C1-C6) alkyl; aryl; heterocyclyl; heteroaryl; cycloalkyl; or SO2R5.
Where substituents R11 and R12 are used, they will be independently selected from the group consisting essentially of hydrogen; (C1-C6) alkyl; hydroxy; (C1-C6) alkoxy; NR6COR5; NR6SO2R5; NR6R5; CF3; F; aryl; heterocyclyl; heteroaryl; cycloalkyl; and cycloalkoxy. R11 may be taken together with R12 to form a cycloalkyl or heterocyclyl ring. R5 and R6 are independently hydrogen; (C1-C6) alkyl; CF3; aryl; cycloalkyl; heteroaryl; or heterocyclyl.
The groups (C1-C6)alkyl, (C1-C6)alkoxy, aryl, heterocyclyl, heteroaryl, cycloalkyl and cycloalkoxy have already been defined in detail above. Within the meaning of these groups it is preferred that R11 and R12 be independently selected from the group consisting of methyl, ethyl, propyl, butyl, iso-butyl, methoxy, cyclopropoxy, cyclopropyl, phenyl, morpholinyl, piperidinyl and pyridyl.
In the portions of the compounds of the present invention represented by partial Formula (1.4.0) above, the moiety E is followed by an optional methylene bridge: (xe2x80x94CH2xe2x80x94)m where m is an integer independently selected from 0 and 1.
The next component of Formula (1.0.0) is represented by xe2x80x9cxe2x80x94(CR7R8)pxe2x80x94xe2x80x9d in which xe2x80x9cpxe2x80x9d is selected from the integers 0 and 1, provided that xe2x80x9cpxe2x80x9d must be selected as 1 where xe2x80x9cBxe2x80x9d is selected as partial formula (1.1.0) through (1.1.11).
The substituent R7 is selected from the group consisting of (C1-C6) alkyl; hydroxy; (C1-C6) alkoxy; NHC(xe2x95x90O)R5; NHSO2R5; NR6R5; F; CF3; OCF3; aryl; heterocyclyl; heteroaryl; cycloalkyl; or R7 may be taken together with R8 to form a cycloalkyl or heterocyclyl ring. The substituent R8 is selected from hydrogen; F; (C1-C6) alkyl or (C1-C6) alkoxy.
The final component of Formula (1.0.0) is the xe2x80x9cxe2x80x94C(xe2x95x90O)OR1xe2x80x9d group wherein R1 is hydrogen.
The compontent represented by partial Formula (1.4.0) includes, but is not limited to, the embodiments which are represented by partial Formulas (1.4.1) through (1.4.20): 
Included within the scope of the present invention are the pharmaceutically acceptable derivatives of the compounds of Formula (1.0.0). The expression xe2x80x9cpharmaceutically acceptable derivativexe2x80x9d as used in the instant specification denotes any pharmaceutically acceptable salt of a compound of Formula (1.0.0). Further included within the scope of the present invention is any other compound which, upon administration to a patient, is capable of directly or indirectly providing a compound of Formula (1.0.0). Such compounds are recognized as prodrugs, and a number of established procedures are available for preparing such prodrug forms of the compounds of Formula (1.0.0).
The term xe2x80x9cpatientxe2x80x9d as used above and throughout the instant specification, refers to mammals, including humans. And where the term xe2x80x9ccellxe2x80x9d is used it refers to mammalian cells, including human cells, unless otherwise specified.
Further included within the scope of the present invention are metabolites or residues of the compounds of Formula (1.0.0) which possess biological activity such that they are able to inhibit cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4. Once synthesized, the inhibitory activities and VLA-4 specificities of the compounds of Formula (1.0.0) according to this invention may be determined using in vitro and in vivo assays which are described in detail further below.
The desirable biological activity of the compounds of Formula (1.0.0) may also be improved by appending thereto appropriate functionalities which will function to enhance existing biological properties of the compound, improve the selectivity of the compound for the existing biological activities, or add to the existing biological activities further desirable biological activities. Such modifications are known in the art and include those which increase biological penetration into a given biological system, e.g., blood, the lymphatic system, and central nervous system; increase oral availability; increase solubility to allow administration by injection; alter metabolism; and alter the rate of excretion of the compound of Formula (1.0.0).
In view of the above definitions and others throughout the instant specification, other chemical and biological terms used herein can be easily understood by those of skill in the art. The defined terms may be used alone or in any combination thereof. The preferred and more preferred chain lengths of the radicals which have been specified herein apply to all such combinations.
Further pursuant to the descriptions above of certain preferred subgeneric and more preferred subgeneric definitions of the compounds of Formula (1.0.0), there follows an enumeration of preferred and more preferred species in order to provide a further illustration of the present invention.
Compounds which include the moiety of partial Formula (1.1.0):
3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-2-methyl-propionic acid
2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-5-yl]-propionic acid
2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-4,5-dihydro-oxazol-5-yl}-propionic acid
2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionic acid
2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-5-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-oxazol-5-yl)-propionic acid
2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionic acid
2-Formylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-thiazol-5-yl}-propionic acid
2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-oxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-oxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-5-yl]-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-4,5-dihydro-oxazol-5-yl}-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-thiazol-5-yl}-propionic acid
3-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-3H-imidazol-4-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-5-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.1):
3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-4-yl]-2-methyl-propionic acid
2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methylbutyl)-4,5-dihydro-oxazol-4-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-oxazol-4-yl]-propionic acid
2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-4,5-dihydro-oxazol-4-yl}-propionic acid
2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-4-yl]-propionic acid
2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-4-yl}-propionic acid
2-(Butane-1-sulfonylamino)3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-oxazol-4-yl)-propionic acid
2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydrooxazol-4-yl]-propionic acid
2-Acetylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-thiazol-4-yl}-propionic acid
2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-oxazol-4-yl)-propionic acid
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-oxazol-4-yl)-propionic acid
2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-4-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-oxazol-4-yl]-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-4,5-dihydro-oxazol-4-yl}-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-thiazol-4-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-oxazol-4-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.2):
3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-5-yl]-2-methyl-propionic acid
2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-5-yl]-propionic acid
2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-oxazol-5-yl}-propionic acid
2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid
2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-5-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-5-yl)-propionic acid
2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid
2-Acetylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiazol-5-yl}-propionic acid
2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-5-yl]-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-oxazol-5-yl}-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiazol-5-yl}-propionic acid
3-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-3H-imidazol-4-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-5-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.3):
3-[2-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-4-yl]-2-methyl-propionic acid
2-Acetylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl -butyl)-oxazol-4-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-4-yl]-propionic acid
2,2-Difluoro-3-{2-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-oxazol -4-yl}-propionic acid
2,2-Dimethyl-3-[2-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-propionic acid
2-Allyloxycarbonylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-4-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(2-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-4-yl)-propionic acid
2-Methyl-3-[2-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-propionic acid
2-Formylamino-3-{2-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiazol-4-yl}-propionic acid
2-Methyl-3-(2-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-4-yl)-propionic acid
2-Benzenesulfonylamino-3-(2-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-4-yl)-propionic acid
2-Benzenesulfonylamino-3-[2-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-propionic acid
2-Methanesulfonylamino-3-[2-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-4-yl]-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-oxazol-4-yl}-propionic acid
2-Acetylamino-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiazol-4-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{2-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-4-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.4):
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-isooxazol-5-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-isoxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-isoxazol-5-yl]-propionic acid
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydroisoxazol-5-yl]-propionic acid
2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methylamino)-methyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-isoxazol-5-yl)-propionic acid
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydroisoxazol-5-yl]-propionic acid
2-Formylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-isothiazol-5-yl}-propionic acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-isoxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-isoxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-isoxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-isoxazol-5-yl]-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-4,5-dihydro-isoxazol-5-yl}-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-isothiazol-5-yl}-propionic acid
3-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-3,4-dihydro-2H-pyrazol-3-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.5):
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-pyrazol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-4,5-dihydro-pyrazol-1-yl]-propionic acid
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl-amino)-ethyl]-4,5-dihydro-pyrazol-1-yl}-propionic acid
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionic acid
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-4,5-dihydro-pyrazol-1-yl)-propionic acid
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionic acid
2-Acetylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-4,5-dihydro-pyrazol-1-yl}-propionic acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-pyrazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-4,5-dihydro-pyrazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-4,5-dihydro-pyrazol-1-yl]-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-4,5-dihydro-pyrazol-1-yl}-propionic acid
2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-pyrazol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4,5-dihydro-pyrazol-1-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.6):
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isooxazol-5-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-5-yl]-propionic acid
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-isoxazol-5-yl}-propionic acid
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-5-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-isoxazol-5-yl)-propionic acid
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
2-Acetylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-isothiazol-5-yl}-propionic acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-5-yl]-propionic acid
2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-isoxazol-5-yl}-propionic acid
2-Acetylamino-3-3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isothiazol-5-yl}-propionic acid
3-Acetylamino-3-(5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-2H-pyrazol-3-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-5-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.7):
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino 3-methyl-butyl)-pyrazol-1-yl]-propionic acid
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-pyrazol-1-yl}-propionic acid
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrazol-1-yl)-propionic acid
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-Formylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-pyrazol-1-yl}-propionic acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-pyrazol-1-yl}-propionic acid
2-Acetylamino-3-{3-[([3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrazol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrazol-1-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.8):
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-2-methyl-propionic acid
2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionic acid
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-oxazol-2-yl}-propionic acid
2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic acid
2-Allyloxycarbonylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-2-yl)-propionic acid
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic acid
2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiazol-2-yl}-propionic acid
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-2-yl)-propionic acid
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-2-yl)-propionic acid
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-oxazol-2-yl}-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiazol-2-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-1H-imidazol-2-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.9):
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-imidazol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-imidazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-imidazol-1-yl]-propionic acid
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-imidazol-1-yl}-propionic acid
2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionic acid
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-imidazol-1-yl)-propionic acid
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionic acid
2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-imidazol-1-yl}-propionic acid
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-imidazol-1-yl) -propionic acid
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-imidazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-imidazol-1-yl]-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-imidazol-1-yl}-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-imidazol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-imidazol-1-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.10):
3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,2,4]oxadiazol-5-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,2,4]oxadiazol-5-yl]-propionic acid
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-[1,2,4]oxadiazol-5-yl}-propionic acid
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-propionic acid
2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]oxadiazol-5-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-[1,2,4]oxadiazol-5-yl)-propionic acid
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-propionic acid
2-Formylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-[1,2,4]thiadiazol-5-yl}-propionic acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-[1,2,4]oxadiazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-[1,2,4]oxadiazol-5-yl)-propionic acid
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]oxadiazol-5-yl]-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]oxadiazol-5-yl}-propionic acid
2-Formylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]thiadiazol-5-yl}-propionic acid
3-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-2H-[1,2,4]triazol-3-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]oxadiazol-5-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.11): 3-[3-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino)-3-methyl-butyl)-[1,2,4]triazol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,2,4]triazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-[1,2,4]triazol-1-yl]-propionic acid
2,2-Difluoro-3-{3-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-[1,2,4]triazol-1-yl}-propionic acid
2,2-Dimethyl-3-[3-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionic acid
2-Allyloxycarbonylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]triazol-1-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(3-{[methyl-(4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-[1,2,4]triazol-1-yl)-propionic acid
2-Methyl-3-[3-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionic acid
2-Acetylamino-3-{3-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-[1,2,4]triazol-1-yl}-propionic acid
2-Methyl-3-(3-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-[1,2,4]triazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-(3-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-[1,2,4]triazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[3-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-[1,2,4]triazol-1-yl]-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-[1,2,4]triazol-1-yl}-propionic acid
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]triazol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,2,4]triazol-1-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.12): 3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-2-methyl-propionic acid
2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-furan-2-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-propionic acid
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl -ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-1H-pyrrol-2-yl}-propionic acid
2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl-pyrrolidin-2-yl)-thiophen-2-yl]-propionic acid
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-furan-2-yl)-propionic acid
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2-yl]-propionic acid
2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiophen-2-yl}-propionic acid
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-1H-pyrrol-2-yl)propionic acid
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-furan-2-yl)-propionic acid
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(3-methyl-1-{([5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2-yl]-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-1H-pyrrol-2-yl}-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiophen-2-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-furan-2-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.13):
3-[5-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-3-yl]-2-methyl-propionic acid
2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-furan-3-yl]-propionic acid
2-Methanesulfonylamino-3-[5-({2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-3-yl]-propionic acid
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-1H-pyrrol-3-yl}-propionic acid
2,2-Dimethyl-3-[5-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-thiophen-3-yl]-propionic acid
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-(4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl-furan-3-yl)-propionic acid
2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-3-yl]-propionic acid
2-Formylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiophen-3-yl}-propionic acid
2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-1H-pyrrol-3-yl)-propionic acid
2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-furan-3-yl)-propionic acid
2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiophen-3-yl]-propionic acid
2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-3-yl]-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-2-methyl-1H-pyrrol-3-yl}-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiophen-3-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-furan-3-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.14):
3-[5-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-2-methyl-propionic acid
2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-furan-2-yl]-propionic acid
2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-thiophen-2-yl]-propionic acid
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-1H-pyrrol-2-yl}-propionic acid
2,2-Dimethyl-3-[5-(1-[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-propionic acid
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-furan-2-yl)-propionic acid
2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2yl]-propionic acid
2-Formylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiophen-2-yl}-propionic acid
2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-1H-pyrrol-2-yl)-propionic acid
2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-furan-2-yl)-propionic acid
2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-thiophen-2-yl]-propionic acid
2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-1H-pyrrol-2-yl]-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-2-methyl-1H-pyrrol-2-yl}-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiophen-2-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-furan-2-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.15):
3-[5-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isooxazol-3-yl]-2-methyl-propionic acid
2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-3-yl]-propionic acid
2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-isoxazol-3-yl]-propionic acid
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-isoxazol-3-yl}-propionic acid
2,2-Dimethyl-3-[5-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionic acid
2-Allyloxycarbonylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-3-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-isoxazol-3-yl)-propionic acid
2-Methyl-3-[5-(1-{([4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionic acid
2-Acetylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-isothiazol-3-yl}-propionic acid
2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-3-yl)-propionic acid
2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-isoxazol-3-yl)-propionic acid
2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionic acid
2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-isoxazol-3-yl]-propionic acid
2-Formylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-4-methyl-isoxazol-3-yl}-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isothiazol-3-yl}-propionic acid
3-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-2H-pyrazol-5-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-isoxazol-3-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.16):
3-[5-(-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-2-methyl-propionic acid
2-Acetylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionic acid
2-Methanesulfonylamino-3-[5-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-oxazol-2-yl]-propionic acid
2,2-Difluoro-3-{5-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-oxazol-2-yl}-propionic acid
2,2-Dimethyl-3-[5-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2yl]-propionic acid
2-Allyloxycarbonylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic acid
2-(Butane-1-sulfonylamino)-3-(5-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-oxazol-2-yl)-propionic acid
2-Methyl-3-[5-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic acid
2-Formylamino-3-{5-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-thiazol-2-yl}-propionic acid
2-Methyl-3-(5-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-2-yl)-propionic acid
2-Benzenesulfonylamino-3-(5-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-oxazol-2-yl)-propionic acid
2-Benzenesulfonylamino-3-[5-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic acid
2-Methanesulfonylamino-3-[5-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-oxazol-2-yl]-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-oxazol-2-yl}-propionic acid
2-Acetylamino-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-thiazol-2-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{5-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-oxazol-2-yl}-propionic acid
2-Acetylamino 3-[5-({2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-methyl)-1H-imidazol-2-yl]-propionic acid
Compounds which include the moiety of partial Formulas (1.1.17), (1.1.18) and (1.1.19):
2-Acetylamino-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-phenyl}-propionic acid
2-Formylamino-3-{6-[1-({3-methoxy-4-[3-(3-methyl-pyridin-2-yl)-ureido]-phenyl}-acetyl)-pyrrolidin-2-yl]-pyridin-2-yl}-propionic acid
3-{4-[1-({3-Ethyl-4-[3-(3-methyl-pyridin-2-yl)-ureido]-phenyl}-acetyl)-pyrrolidin-2-yl]-pyrimidin-2-yl}-propionic acid
2-Acetylamino-3-[3-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-phenyl]-propionic acid
2-Acetylamino-3-[3-({2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-methyl)-phenyl]-propionic acid
2-{2-[({[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyridin-4-ylmethyl}-4-methyl-pentanoic acid
3-{2-[(Methyl-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-amino)-methyl]-pyridin-4-yl}-propionic acid
2-Methanesulfonylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-[1,3,5]triazin-2-yl}-propionic acid
1-[4-(1-{[6-(3-Pyridin-2-yl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-pyridin-2-ylmethyl]-cyclopropanecarboxylic acid
3-[3-(1-{[6-(3-Pyridin-2-yl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-phenyl]-butyric acid
2-(Butane-1-sulfonylamino)-3-{3-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-phenyl}-propionic acid
2-Benzenesulfonylamino-3-[3-({[(2-methoxy-2xe2x80x2-methyl-biphenyl-4-yl)-acetyl]-methyl-amino}-methyl)-phenyl]-propionic acid
Compounds which include the moiety of partial Formula (1.1.20):
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrrol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrrol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrrol-1-yl]-propionic acid
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-pyrrol-1-yl}-propionic acid
2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1yl]-propionic acid
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrrol-1-yl)-propionic acid
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1-yl]-propionic acid
2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-pyrrol-1-yl}-propionic acid
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrrol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrrol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-pyrrol-1-yl]-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-pyrrol-1-yl}-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrrol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrrol-1-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.21):
3-[4-(1-{2-[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-2-methyl-propionic acid
2-Acetylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(1-{2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-3-methyl-butyl)-pyrazol-1-yl]-propionic acid
2,2-Difluoro-3-{4-[1-(methyl-{[6-(3-o-tolyl-ureido)-pyridin-3-yl]-acetyl}-amino)-ethyl]-pyrazol-1-yl}-propionic acid
2,2-Dimethyl-3-[4-(1-{[6-(3-phenyl-ureido)-pyridin-3-yl]-acetyl-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-(Butane-1-sulfonylamino)-3-(4-{[methyl-({4-[3-(3-methyl-pyridin-2-yl)-ureido]-piperidin-1-yl}-acetyl)-amino]-methyl}-pyrazol-1-yl)-propionic acid
2-Methyl-3-[4-(1-{[4-(2-methyl-benzyloxy)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-Formylamino-3-{4-[1-(biphenyl-4-yl-acetyl)-pyrrolidin-2-yl]-pyrazol-1-yl}-propionic acid
2-Methyl-3-(4-{1-[(4-o-tolyloxy-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-(4-{1-[(4-phenoxymethyl-phenyl)-acetyl]-pyrrolidin-2-yl}-pyrazol-1-yl)-propionic acid
2-Benzenesulfonylamino-3-[4-(1-{[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-Methanesulfonylamino-3-[4-(3-methyl-1-{[5-(3-o-tolyl-ureido)-pyridin-2-yl]-acetyl}-pyrrolidin-2-yl)-pyrazol-1-yl]-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-5-methyl-pyrazol-1-yl}-propionic acid
2-Acetylamino-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrazol-1-yl}-propionic acid
2-(2,6-Dichloro-benzoylamino)-3-{4-[({[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-pyrazol-1-yl}-propionic acid
Compounds which include the moiety of partial Formula (1.1.22):
2-[({[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-benzooxazole-6-carboxylic acid
2-[1-(2-3-Methoxy-4-[3-(3-methyl-pyridin-2-yl)-ureido]-phenyl}-acetylamino)-3-methyl-butyl]-3H-benzoimidazole-5-carboxylic acid
2-(1-{[4-(3-Pyridin-2-yl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-1H-imidazo[4,5-c]pyridine-6-carboxylic acid
2-(1-{[3-Ethoxy-4-(3-pyridin-2-yl-ureido)-phenyl]-acetyl}-pyrrolidin-2-yl)-benzothiazole-6-carboxylic acid
2-[({[3-Methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetyl}-methyl-amino)-methyl]-benzothiazole-6-carboxylic acid
2-({[(4-Benzyloxy-phenyl)-acetyl]-methyl-amino}-methyl)-oxazolo[5,4]pyridine-5-carboxylic acid
3-Methyl-2-{1-[(4-phenoxy-phenyl)-acetyl]-pyrrolidin-2-yl}-3H-benzoimidazole-5-carboxylic acid
The above-described compounds of the present invention may be utilized in the form of acids, esters, or other chemical classes of compounds to which the compounds described belong. It is also within the scope of the present invention to utilize those compounds in the form of pharmaceutically acceptable salts derived from various organic and inorganic acids and bases in accordance with procedures well known in the art. Such well-known pharmaceutically acceptable salts include, but are not limited to acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, besylate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecysulfate, ethanesulfonate, fumarate, glucoheptanoate, gluconate, glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, isethionate, lactate, lactobionate, maleate, mandelate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphonate, picrate, pivalate, propionate, salicylate, sodium phosphate, stearate, succinate, sulfate, sulfosalicylate, tartrate, thiocyanate, thiomalate, tosylate, and undecanoate.
Base salts of the compounds of the present invention include, but are not limited to ammonium salts; alkali metal salts such as sodium and potassium; alkaline earth metal salts such as calcium and magnesium; salts with organic bases such as dicyclohexylamine, meglumine, N-methyl-D-glucamine, tris-(hydroxymethyl)-methylamine (tromethamine), and salts with amino acids such as arginine, lysine, etc. Compounds of the present invention which comprise basic nitrogen-containing groups may be quaternized with such agents as (C1-C4) alkyl halides, e.g., methyl, ethyl, iso-propyl and tert-butyl chlorides, bromides and iodides; di(C1-C4) alkyl sulfate, e.g., dimethyl, diethyl and diamyl sulfates; (C10-C18) alkyl halides, e.g., decyl, dodecyl, lauryl, myristyl and and stearyl chlorides, bromides and iodides; and aryl-(C1-C4) alkyl halides, e.g., benzyl chloride and phenethyl bromide. Such salts permit the preparation of both water-soluble and oil-soluble compounds of the present invention.
Among the above-recited pharmaceutical salts those which are preferred include, but are not limited to acetate, mesylate, citrate, fumarate, gluconate, hemisuccinate, hippurate, hydrochloride, hydrobromide, isothionate, mandelate, meglumine, nitrate, oleate, phosphonate, pivalate, sodium phosphate, stearate, sulfate, sulfosalicylate, tartrate, thiomalate, tosylate, and trimethylamine.
Multiple salts forms are included within the scope of the present invention where a compound of the present invention contains more than one group capable of forming such pharmaceutically acceptable salts. Examples of typical multiple salt forms include, but are not limited to bitartrate, diacetate, difumarate, dimeglumine, diphosphate, disodium, and trihydrochloride.
The pharmaceutical compositions of the present invention comprise any one or more of the above-described inhibitory compounds of the present invention, or a pharmaceutically acceptable salt thereof as also above-described, together with a pharmaceutically acceptable carrier in accordance with the properties and expected performance of such carriers which are well-known in the pertinent art.
The term xe2x80x9ccarrierxe2x80x9d as used herein includes acceptable diluents, excipient, adjuvants and vehicles. Pharmaceutically acceptable carriers that may be used in the pharmaceutical compositions of this invention include but are not limited to, ion exchange compositions; alumina; aluminum stearate; lecithin; serum proteins, e.g., human serum albumin; phosphates; glycine; sorbic acid; potassium sorbate; partial glyceride mixtures of saturated vegetable fatty acids; water; salts or electrolytes, e.g., prolamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica; magnesium trisilicate; polyvinyl pyrrolidone; cellulose-based substances; e.g., sodium carboxymethylcellulose; polyethylene glycol; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; and wool fat.
More particularly, the diluents, excipient, adjuvants and vehicles used in the pharmaceutical compositions of the present invention comprise members selected from the groups consisting essentially of the following: acidifying and alkalizing agents added to obtain a desired or predetermined pH comprise acidifying agents, e.g., acetic acid, glacial acetic acid, malic acid, and propionic acid, and alkalizing agents, e.g., edetol, potassium carbonate, potassium hydroxide, sodium borate, sodium carbonate, and sodium hydroxide; aerosol propellants required where the pharmaceutical composition is to be delivered as an aerosol under significant pressure, e.g., acceptable halogenated hydrocarbons; nitrogen; or a volatile hydrocarbon such as butane, propane, isobutane or mixtures thereof; antimicrobial agents including antibacterial, antifungal and antiprotozoal agents added where the pharmaceutical composition is topically applied, e.g., antimicrobial agents such as benzyl alcohol, chlorobutanol, phenylethyl alcohol, phenylmercuric acetate, potassium sorbate, and sorbic acid, and antifungal agents such as benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, and sodium benzoate; antimicrobial preservatives added to the pharmaceutical compositions in order to protect them against the growth of potentially harmful microorganisms, e.g., alkyl esters of p-hydroxybenzoic acid, propionate salts, phenoxyethanol, methylparaben sodium, propylparaben sodium, sodium dehydroacetate, benzalkonium chloride, benzethonium chloride, and benzyl alcohol; antioxidants added to protect all of the ingredients of the pharmaceutical composition from damage or degradation by oxidizing agents present in the composition itself or the use environment, e.g., anoxomer, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorous acid, potassium metabisulfite, propyl octyl and dodecyl gallate, sodium metabisulfite, sulfur dioxide, and tocopherols; buffering agents used to maintain a desired pH of a composition once established, e.g., calcium acetate, potassium metaphosphate, potassium phosphate monobasic, and tartaric acid; and chelating agents used to help maintain the ionic strength of the pharmaceutical composition and bind to and effectively remove destructive compounds and metals, e.g., edetate dipotassium, edetate disodium, and edetic acid.
Dermatologically active agents are added to the pharmaceutical compositions of the present invention to be applied topically, e.g., wound healing agents such as peptide derivatives, yeast, panthenol, hexylresorcinol, phenol, tetracycline hydrochloride, lamin and kinetin, glucocorticosteroids for treating inflammation, e.g., hydrocortisone, dexamethasone, betamethasone, triamcinolone, fluocinolone and methylprednisolone, retinoids for treating acne, psoriasis, cutaneous aging, and skin cancer, e.g., retinol, tretinoin, isotretinoin, etretinate, acitretin, and arotinoid, immunosuppressive agents for treating inflammation, e.g., dapsone and sulfasalazine; mild antibacterial agents, e.g., resorcinol, salicylic acid, benzoyl peroxide, erythromycin-benzoyl peroxide, erythromycin, clindamycin, and mupirocin, antifungal agents, e.g., griseofulvin, azoles such as miconazole, econazole, itraconazole, fluconazole, and ketoconazole, and allylamines such as naftifine and terfinafine, antiviral agents, e.g., acyclovir, famciclovir, and valacyclovir, antihistamines, e.g., diphenhydramine, terfenadine, astemizole, loratadine, cetirizine, acrivastine, and temelastine, topical anesthetics, e.g., benzocaine, lidocaine, dibucaine, and pramoxine hydrochloride, topical analgesics, e.g., methyl salicylate, camphor, menthol, and resorcinol; topical antiseptics for preventing infection, e.g., benzalkonium chloride and povidone-iodine; vitamins and derivatives thereof such as tocopherol, tocopherol acetate, retinoic acid and retinol.
Further examples of diluents, excipient, adjuvants and vehicles used in the pharmaceutical compositions of the present invention comprise members selected from the groups consisting essentially of the following: dispersing and suspending agents, e.g., poligeenan, povidone, and silicon dioxide; emollients, e.g., hydrocarbon oils and waxes, triglyceride esters, acetylated monoglycerides, methyl and other alkyl esters of C10-C20 fatty acids, C10-C20 fatty acids, C10-C20 fatty alcohols, lanolin and derivatives, polyhydric alcohol esters such as polyethylene glycol (200-600), polyoxyethylene sorbitan fatty acid esters, wax esters, phospholipids, and sterols; emulsifying agents used for preparing oil-in-water emulsions; excipients, e.g., laurocapram and polyethylene glycol monomethyl ether; humectants, e.g., sorbitol, glycerin and hyaluronic acid; ointment bases, e.g., petrolatum, polyethylene glycol, lanolin, and poloxamer; penetration enhancers, e.g., dimethyl isosorbide, diethyl-glycol-monoethylether, 1-dodecylazacycloheptan-2-one, and dimethylsulfoxide (DMSO); preservatives, e.g., benzalkonium chloride, benzethonium chloride, alkyl esters of p-hydroxybenzoic acid, hydantoin derivatives, cetylpyridinium chloride, propylparaben, quaternary ammonium compounds such as potassium benzoate, and thimerosal; sequestering agents comprising cyclodextrins; solvents, e.g., acetone, alcohol, amylene hydrate, butyl alcohol, corn oil, cottonseed oil, ethyl acetate, glycerin, hexylene glycol, isopropyl alcohol, isostearyl alcohol, methyl alcohol, methylene chloride, mineral oil, peanut oil, phosphoric acid, polyethylene glycol, polyoxypropylene 15 stearyl ether, propylene glycol, propylene glycol diacetate, sesame oil, and purified water; stabilizers, e.g., calcium saccharate and thymol; surfactants, e.g., lapyrium chloride; laureth 4, i.e., xcex1-dodecyl-xcfx89-hydroxy-poly(oxy-1,2-ethanediyl) or polyethylene glycol monododecyl ether.
According to this invention, the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as do natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as Rh, HClX or similar alcohol.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.
Topical application for the lower intestinal tract can be effected in a rectal suppository formulation, as described above, or in a suitable enema formulation. Topically active transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspension in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation through the use of a nebulizer, a dry powder inhaler or a metered dose inhaler. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, hydrofluorocarbons, and/or other conventional solubilizing or dispersing agents.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, and the particular mode of administration. It should be understood, however, that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredient may also depend upon the therapeutic or prophylactic-agent, if any, with which the ingredient is co-administered.
The dosage and dose rate of the compounds of this invention effective for preventing, inhibiting, suppressing or reducing cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4 will depend on a variety of factors, such as the nature of the inhibitor, the size of the patient, the goal of the treatment, the nature of the pathology to be treated, the specific pharmaceutical composition used, and the observations and conclusions of the treating physician.
For example, where the dosage form is oral, e.g., a tablet or capsule, suitable dosage levels of the compounds of Formula (1.0.0) will be between about 1.0 xcexcg and about 10.0 mg/kg body weight per day, preferably between about 5.0 xcexcg and about 5.0 mg/kg body weight per day, more preferably between about 10.0 xcexcg and about 1.0 mg/kg of body weight per day, and most preferably between about 20.0 xcexcg and about 0.5 mg/kg of body weight per day of the active ingredient.
Where the dosage form is topically administered to the bronchia and lungs, e.g., by means of a powder inhaler or nebulizer, suitable dosage levels of the compounds of Formula (1.0.0) will be between about 0.1 xcexcg and about 1.0 mg/kg body weight per day, preferably between about 0.5 xcexcg and about 0.5 mg/kg body weight per day, more preferably between about 1.0 xcexcg and about 0.1 mg/kg of body weight per day, and most preferably between about 2.0 xcexcg and about 0.05 mg/kg of body weight per day of the active ingredient.
Using representative body weights of 10 kg and 100 kg in order to illustrate the range of daily topical dosages which might be used as described above, suitable dosage levels of the compounds of Formula (1.0.0) will be between about 1.0-10.0 xcexcg and 10.0-100.0 mg per day, preferably between about 5.0-50.0 xcexcg and 5.0-50.0 mg per day, more preferably between about 10.0-100.0 xcexcg and 1.0-10.0 mg per day, and most perferably between about 20.0-200.0 xcexcg and about 0.5-5.0 mg per day of the active ingredient comprising a compound of Formula (1.0.0). These ranges of dosage amounts represent total dosage amounts of the active ingredient per day for a given patient. The number of times per day that a dose is administered will depend upon such pharmacological and pharmacokinetic factors as the half-life of the active ingredient, which reflects its rate of catabolism and clearance, as well as the minimal and optimal blood plasma or other body fluid levels of said active ingredient attained in the patient which are required for therapeutic efficacy
Numerous other factors must also be considered in deciding upon the number of doses per day and the amount of active ingredient per dose which will be administered. Not the least important of such other factors is the individual respsonse of the patient being treated. Thus, for example, where the active ingredient is used to treat or prevent asthma, and is administered topically via aerosol inhalation into the lungs, from one to four doses consisting of acuations of a dispensing device, i.e., xe2x80x9cpuffsxe2x80x9d of an inhaler, will be administered each day, each dose containing from about 50.0 xcexcg to about 10.0 mg of active ingredient.
Included within the scope of the present invention are embodiments comprising compositions which contain, in addition to a compound of the present invention as active ingredient, additional therapeutic agent active ingredients selected from the group consisting essentially of anti-inflammatory corticosteroids; bronchodilators; antiasthmatics; non-steroidal anti-inflammatories; immunosuppressants; immunostimulants; antimetabolites; antipsoriatics and antidiabetics. Specific compounds within each of these classes may be selected from those listed under the appropriate headings in Comprehensive Medicinal Chemistry, Pergamon Press, Oxford, England, pp. 970-986 (1990); and Goodman and Gilman""s The Pharmacological Basis of Therapeutics, 9th ed., Hardman, J. G. and Limbird, L. E., eds., McGraw-Hill, 1996, the disclosure of which are incorporated herein by reference in their entireties. Especially preferred active ingredients to be included for use in combination with the compounds of Formula (1.0.0) are anti-inflammatory compounds such as theophylline, sulfasalazine and aminosalicylates; immunosuppressants such as cyclosporin, FK-506, and rapamycin; antimetabolites such as cyclophosphamide and methotrexate; and immunomodulators such as the interferons.
Still further embodiments of the present invention relate to a method of treating or preventing an inflammatory, autoimmune or respiratory disease by inhibiting cell adhesion and consequent or associated pathogenic processes subsequently mediated by VLA-4. As already mentioned, VLA-4-associated cell adhesion plays a central role in a variety of inflammatory, immune and autoimmune diseases. Thus, inhibition of cell adhesion by the compounds of this invention may be utilized in methods of treating or preventing inflammatory, immune and autoimmune diseases. Preferably the diseases to be treated with the methods of this invention are selected from asthma, arthritis, psoriasis, transplantation rejection, multiple sclerosis, diabetes and inflammatory bowel disease.
The above-described methods of treatment of the present invention may employ the compounds of Formula (1.0.0) in the form of monotherapy, but said methods may also be used in the form of multiple therapy in which one or more compounds of Formula (1.0.0) are coadministered in combination with a known anti-inflammatory, immunomodulating, immunostimulating or immunosuppressive agent. The terms xe2x80x9ccoadministeredxe2x80x9d or xe2x80x9ccoadministrationxe2x80x9d as used herein are intended to mean therapeutic utilization of one or more compounds of Formula (1.0.0) in combination with one or more additional therapeutic agents, including but not limited to, administration of the combination of therapeutic active agents in a single dosage form or in multiple dosage forms representing the same or different routes of administration, said multiple dosage forms being administered at substantially the same time or at different times.
Subsequent to synthesis of any of the above-recited preferred species of the present invention or any other compounds falling within the scope of the present invention, the biological activities relating to the VLA-4 specificities of said compounds may be determined using one or more of the numerous in vitro and in vivo assays which have been described heretofore in the technical literature pertinent to the art. For example, some of the now very-well established assay methods and models concern measurement of VLA-4 activity by determining the concentration of a test candidate inhibitor required to block the binding of VLA-4-expressing cells to fibronectin- or CS-1 coated plates. In this assay microtiter wells are coated with either fibronectin (containing the CS-1 sequence), CS-1 peptide or soluble VCAM-1. Once the wells are coated, varying concentrations of the test compound are then added together with appropriately labelled, VLA-4-expressing cells. Alternatively, the test compound may be added first and allowed to incubate with the coated wells prior to the addition of the cells. The cells are allowed to incubate in the wells for at least 30 minutes. Following incubation, the wells are emptied and washed. Inhibition of binding is measured by quantitating the fluorescence or radioactivity bound to the plate for each of the various concentrations of test compound, as well as for controls containing no test compound. However, the assay just described is less preferred than other assays mentioned further below in determining the VLA-4 activity of the compounds of Formula (1.0.0).
VLA-4-expressing cells that may be utilized in this assay include Ramos cells, Jurkat cells, A375 melanoma cells, as well as human peripheral blood lymphocytes (PBL). The cells used in this assay may be fluorescently or radioactively labelled.
In order to assess the VLA-4 inhibitory specificity of test compounds, assays for other major groups of integrins, i.e., xcex22 and xcex23, as well as other xcex21 integrins, such as VLA-5, VLA-6 and xcex14xcex27 may be performed. These assays may be similar to the adhesion inhibition and direct binding assays described above, substituting the appropriate integrin-expressing cell and corresponding ligand. For example, polymorphonuclear cells (PMNs) express xcex22 integrins on their surface and bind to ICAM; while xcex23 integrins are involved in platelet aggregation and inhibition may be measured in a standard platelet aggregation assay. VLA-5 binds specifically to Arg-Gly-Asp sequences, while VLA-6 binds to laminin. Further, xcex14xcex27 is a recently discovered homologue of VLA-4, which also binds fibronectin and VCAM as well as MAdCAM-1. Specificity with respect to xcex14xcex27 is determined in a binding assay that utilizes CS-1, VCAM or MAdCAM-1 and a cell line that expresses xcex14xcex27, but not VLA-4, such as RPMI-8866 cells.
Once VLA-4-specific inhibitors are identified, they may be further characterized in in vivo assays. One such assay tests the inhibition of allergen induced airway hyperresponsiveness and cell influx, such as described by Henderson et al., xe2x80x9cBlockade of CD49d (xcex14 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model of asthmaxe2x80x9d, J. Clin. Invest., 100(12), pp. 3083-92 (1997). In this assay, mice are sensitized by ip exposure to an irritant, such as ovalbumin. Following a recovery period, the mice are challenged by aerosol exposure to the allergen. Before aerosol exposure, the mice are given various doses of the VLA-4 inhibitor by intratracheal injection. In vivo inhibition of cell adhesion associated inflammation is assessed by measuring the number of cells and cytokines in the bronchial alveolar lavage fluid. In this manner, one may identify those inhibitors of this invention which are best suited for inhibiting inflammation.
Another in vivo assay that may be employed is the primate asthma assay. This assay is performed essentially as described in Turner, C. R., et al., xe2x80x9cCharacterization of a primate model of asthma using anti-allergy/anti-asthma agentsxe2x80x9d, Inflammation Research, 45(5), pp. 239-45 (1996), the disclosure of which is incorporated herein by reference in its entirety. This assay measures inhibition of Ascaris antigen-induced late phase airway responses and airway hyperresponsiveness in allergic primates following administration of anti-allergy/anti-asthma agents.
The compounds of the present invention may be formulated into pharmaceutical compositions that may be administered orally, parenterally, by inhalation (metered dose inhaler, dry powder inhaler or nebulizer), topically, rectally, nasally, intraocularly, buccally, vaginally or via an implanted reservoir. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
The compounds of Formula (1.0.0) may be prepared in accordance with well-known procedures for carrying out the synthesis of organic compounds which are non-peptidyl or semi-peptidyl in nature. A number of different procedures are available which are fully disclosed in the technical literature and with which the skilled artisan will be familiar. The description which follows of several such synthesis schemes is merely representative and not intended to be in any way limiting. A number of abbreviations are used in said description in order to conserve space. Although these abbreviations are also well known to the artisan, they are set out immediately below for clarity and convenience:

The synthesis of compounds of the Formula 1.0.0 in which the xe2x80x9cBxe2x80x9d component is an isoxazole ring and the xe2x80x9cYxe2x80x9d component is xe2x80x94SO2xe2x80x94 is illustrated in Scheme 1, steps A through G. In Scheme 1, step A, the starting material, diethyl amino malonate, is commercially available, e.g., from Aldrich Chemical Company, Milwaukee, Wis. 53233. The amide product (2.0.1), where R5 is hydrogen, methyl or phenyl, is also commercially available. Other amides, where R5 is alkyl, aryl, heterocyclyl or heteroaryl are made readily available by the reaction of the appropriate acid chloride with the amine (2.0.0) using the conditions that are well described in the literature (e.g. March, J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 3rd edition, 1985). Under similar conditions, the amine (2.0.0) may be converted to its corresponding sulfonamide by the reaction of 2.0.0 with an alkyl or aryl sulfonyl chloride. The carbamate product (2.0.1), where R5 is alkoxy or aryloxy is prepared from amine 2.0.0 in accordance with procedures described by Paik, Yi Hyon; Dowd, Paul; J. Org. Chem. 1986, 51(15), 2910-2913; and Kawai, Masao; Nyfeler, Rolf; Berman, Judd M.; Goodman, Murray; J. Med. Chem., 1982 25(4), 397-402.
In Scheme 1, Step B, the intermediate 2.0.3 is prepared from the oxime 2.0.2. Oxime 2.0.2 is prepared from its corresponding aldehyde by procedures well known to those skilled in the art (e.g. Chung, Yong Jun; Ryu, Eun Jung; Keum, Gyochang; Kim, Byeang Hyean; Bioorg.Med.Chem.; 1996, 4(2) 209-226; and Kim, Byeang Hyean; Chung, Yong Jun; Keum, Gyochang; Kim, Jaheon; Kim, Kimoon; Tetrahedron Lett.; 1992, 33(45); 6811-6814). Oxime 2.0.2 is converted to the isoxazole 2.0.3 by oxidation with a suitable oxidant such as sodium hypochlorite, tert-butyl hypochlorite, or N-chlorosuccinimide in a suitable solvent such as THF, chloroform or methylene chloride; and reacting the resulting nitrile N-oxide in situ with propargyl bromide. This [2+3] cycloaddition reaction is well known in the literature as a method for preparing the isoxazole ring structure. See, e.g., Synthesis, 508-9, 1982.
In Scheme 1, Step C, the bromide intermediate 2.0.3 is converted to the isoxazole containing component 2.0.4. The bromide 2.0.3 is reacted with an optionally substituted malonate (2.0.1) in a suitable solvent such as DMF, DMSO or methylene chloride, in the presence of a base such as triethlyamine or cesium carbonate. DMF is the preferred solvent and cesium carbonate is the preferred base. The reaction is performed at a temperature between 0 and 30xc2x0 C. for a period of 1 to 16 hours. The reaction of bromide 2.0.3 with malonate 2.0.1 in Scheme 1, step C, is not limited to 2-amino malonates, but can be expanded to include malonates of the formula [EtOC(xe2x95x90O)CHR7C(xe2x95x90O)OEt], where R7 is defined above in the definition of Formula 1.0.0.
The synthesis of the mono ester intermediate 2.0.5 is illustrated in Scheme 1, Step D. The diethyl malonate 2.0.4 is converted to its half-ester intermediate by reaction with one equivalent of a suitable base such as aqueous sodium hydroxide or lithium hydroxide in a solvent such as THF, methanol, tert-butanol or dioxane. The use of aqueous sodium hydroxide in dioxane is preferred. The reaction is conducted at a temperature between 0 and 50xc2x0 C. for a time period of between 1 and 16 hours. Three hours at ambient temperature is preferred. This half-ester intermediate is subsequently transformed to mono ester 2.0.5 in situ by heating it in a suitable solvent such as benzene, toluene or dioxane at a temperature between 0 and 200xc2x0 C. for a time period of between 1 and 16 hours. Heating at 125xc2x0 C. for 3 hours in dioxane is preferred. 
The synthesis of the amine intermediate 2.0.6 is illustrated in Scheme 1, Step E. The tert-butyloxycarbamate intermediate 2.0.5 is reacted with an acid such as neat trifluoroacetic acid, or a solution hydrochloric acid in a suitable non-aqueous solvent such as dioxane. The reaction is conducted at a temperature between 0 and 50xc2x0 C. for a time period of between 1 and 16 hours. Hydrochloric acid in dioxane at ambient temperature for 1 hour is the preferred conditions. It will be recognized by those skilled in the art that the tert-butyloxycarbonyl group serves as a protecting group for the amine and that other suitable protecting groups can be employed. It will be further recognized that methods for removal of these protecting groups must be compatible with all the functionality present in R5. These methods are well-known in the technical literature of the relevant art. For example, see Greene, T. W., Wuts, P. G. M. Protective Group in Organic Synthesis; John Wiley and Sons: New York, 1991.
The synthesis of the sulfonamide intermediate 2.0.7 is described in scheme 1 step F. The amine 2.0.6 is reacted with a sulfonyl chloride [A(CH2)nxe2x80x94SO2Cl, where xe2x80x9cAxe2x80x9d and xe2x80x9cnxe2x80x9d are defined above in the definition of formula 1.0.0] in a solvent such as dichloromethane, water, or pyridine with or without a base such as sodium carbonate or diisopropylethylamine. The reaction is conducted at a temperature between 0 and 50xc2x0 C. for a period of between 1 and 16 hours. The preferred conditions are sodium carbonate in water at ambient temperature for 16 hours. 
The carboxylic acid product is prepared from ester intermediate 2.0.7 as illustrated in scheme 1, step G. The ester intermediate 2.0.7 is reacted with a suitable aqueous base, such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a solvent such as tert-butanol, methanol, and/or THF. The reaction is conducted at a temperature between 0 and 50xc2x0 C. for a time period between 0.5 and 24 hours. Aqueous lithium hydroxide in a mixture of THF and methanol at ambient temperature for 1 hour are the preferred conditions.
The above-described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme 1-xcex1, Steps A through G with reference to a particular compound of the present invention: 
The following schematic synthesis diagram illustrates a generalized preparation process for the compounds of Formula 1.0.0 in which the xe2x80x9cYxe2x80x9d component is Cxe2x95x90O: 
The starting material A1xe2x80x94NCO is an isocyanate in which xe2x80x9cA1xe2x80x9d has the same definition as the A component of Formula (1.0.0) regarding the aryl, heteroaryl and heterocyclyl moieties substituted with 0 to 3 R9. Isocyanate starting materials for making component A, such as phenyl isocyanate, o-tolyl isocyanate, 2-fluorophenyl isocyanate and 2-chlorophenyl isocyanate are commercially available, e.g., from Aldrich Chemical Company, Milwaukee, Wis. 53233. Alternatively, isocyanate starting materials can be readily prepared from their corresponding amines using the methods described in the literature (e.g. March, J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 3rd edition, 1985). Pyridyl analogues of the above phenyl isocyanates can be used to prepare the corresponding compounds of Formula (1.0.0) where the A component contains a pyridyl group.
One of the above-described isocyantes is reacted with an amine of formula 2.0.10. The addition of amines to isocyanates is a well-known reaction which provides substituted ureas in a facile manner. The reaction can be carried out in a solvent such as methylene chloride with triethylamine at slightly elevated temperatures. The disubstituted urea (2.0.11) prepared as in the above-indicated reaction scheme, which forms the reactant eventually resulting in component A of the compounds of Formula (1.0.0), is next reacted with an amine of the formula xe2x80x9cxe2x80x94NR4CR2R3xe2x80x94Bxe2x80x9d, in which xe2x80x9cBxe2x80x9d is defined as one of the partial Formulas (1.1.0)-(1.1.22). 
The reaction between the component A forming reactant (2.0.11) and the amine 2.0.6 will be recognized by the artisan as one involving the acylation of an amine by a carboxylic acid which can be made to proceed in good yield at room temperature or slightly above by the use of coupling agents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) and 1-hydroxybenzotriazole (HOBT); dicyclohexylcarbodiimide (DCCl); N,Nxe2x80x2-carbonyldiimidazole; N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl(succinimido)uronium tetrafluoroborate; and benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate (BOP). The amine component (2.0.6) is available as described in Scheme 1. This reaction may be illustrated in the above schematic synthesis diagram which provides a generalized preparation process for the compounds of Formulas (1.0.0).
To prepare the final product of Formula (1.0.0) in the form of the acid, an additional step is required, as is shown in the following reaction scheme: 
The final acid product (2.0.13) is prepared from ester 2.0.12 as illustrated in the above scheme. The intermediate is reacted with a suitable aqueous hydroxide base, such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a solvent system comprised of tert-butanol, methanol or THF and methanol. The reaction is conducted at a temperature between 0 and 50xc2x0 C. for 0.5 to 16 hours. Lithium hydroxide in THF, methanol, and water at ambient temperature for 1 hour are the preferred conditions.
The above-described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme 2-xcex1, Steps A through C with reference to a particular compound of the present invention: 
An alternative synthesis of compounds of the Formula (1.0.0) is illustrated in Synthesis Scheme 3, steps A through C. The synthesis of the amine intermediate 2.0.14 is illustrated in scheme 3, step A. Tert-butyloxycarbamate intermediate 2.0.4 is reacted with an acid such as neat trifluoroacetic acid, or a solution hydrochloric acid in a suitable non-aqueous solvent such as dioxane. The reaction is conducted at a temperature between 0 and 50xc2x0 C. for a time period of between 1 and 16 hours. Hydrochloric acid in dioxane at ambient temperature for 1 hour are the preferred conditions. It will be recognized by those skilled in the art that the tert-butyloxycarbonyl group serves as a protecting group for the amine and that other suitable protecting groups can be employed. It will be further recognized that methods for removal of these protecting groups must be compatible with all of the functionality present in R5. These methods are well-known in the technical literature of the relevant art. For example, see Greene, T. W., Wuts, P. G. M. Protective Group in Organic Synthesis; John Wiley and Sons: New York, 1991.
In scheme 3, step B, the amine 2.0.14 is reacted with acid 2.0.15 under the same 15 conditions as synthesis Scheme 2, step B.
To prepare the final product of Formula (1.0.0) in the form of the acid, an additional step is required, as is shown in the following reaction scheme: 
The final acid product (2.0.17) is prepared from ester 2.0.16 as illustrated in the above scheme. The intermediate is reacted with a suitable aqueous hydroxide base, such as lithium hydroxide, potassium hydroxide or sodium hydroxide in a solvent system comprised of tert-butanol, methanol or THF and methanol. The reaction is conducted at a temperature between 0 and 50xc2x0 C. for 0.5 to 16 hours. Lithium hydroxide in THF, methanol, and water at ambient temperature for 1 hour are the preferred conditions.
The above-described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme 3-xcex1, Steps A through C with reference to a particular compound of the present invention: 
An alternative mode for the synthesis of compounds of the Formula (1.0.0) is illustrated in Synthesis Scheme 4, Steps A through D. 
In Scheme 4, Step A, the oxime 2.0.2 is converted to the isoxazole 2.0.18 by oxidation with a suitable oxidant such as sodium hypochlorite, tert-butyl hypochlorite, or N-chlorosuccinimide in a suitable solvent such as THF, chloroform or methylene chloride; and reacting the resulting nitrile N-oxide in situ with a 2,2-disubstituted methyl pent-4-ynoate. This [2+3] cycloaddition reaction is well known in the literature as a method for preparing the isoxazole ring structure. See, e.g., Synthesis, 508-9, 1982.
The synthesis of the amine intermediate 2.0.19 is illustrated in the above reaction scheme using the same conditions as Scheme 3, step A. The starting material is the tert-5 butyloxycarbamate intermediate 2.0.18.
In scheme 4, step C, the amine 2.0.19 is reacted with acid 2.0.15 under the same conditions as synthesis Scheme 2, step B. This reaction may be illustrated in the above schematic synthesis diagram which provides a generalized preparation process for the compounds of Formulas (1.0.0).
To prepare the final product of Formula (1.0.0) in the form of the acid, an additional step is required, as is shown in the following reaction scheme: 
The final acid product 2.0.21 was prepared from ester 2.0.20 as illustrated in the above scheme using the method of Scheme 3, step C.
The above-described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme 4-xcex1, Steps A through C with reference to a particular compound of the present invention: 
An alternative mode for the synthesis of compounds of the Formula (1.0.0) is 5 illustrated in Synthesis Scheme 5 Steps A through D. 
The bromide 2.0.22 is available commercially from, for example, from Aldrich Chemical Company, Milwaukee, Wis. 53233. Bromide 2.0.22 is converted into the desired diester containing component 2.0.23, as shown in the above scheme. The bromide is reacted with an amino malonate under the conditions described in scheme 1, step C. 
The nitrile 2.0.23 is converted to the desired amine 2.0.24 as illustrated in the above reaction scheme. The nitrile 2.0.23 is reduced to the corresponding amine 2.0.24 by hydrogenation as described in the literature (e.g. March, J. xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 3rd edition, 1985).
The above-described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme 5-xcex1: 
The synthesis of bicyclic compounds of the Formula (1.0.0) is illustrated in Synthesis Scheme 6 Steps A through D. Starting materials are acids and amines available from commercial sources, eg., Aldrich Chemical Company, Milwaukee, Wis. 53233.
The reaction illustrated in the above scheme will be recognized by the artisan as one involving the acylation of an amine 2.0.22 by a carboxylic acid 2.0.23 which can be made to proceed in good yield at room temperature or slightly above by the use of coupling agents such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) and 1-hydroxybenzotriazole (HOBT); dicyclohexylcarbodiimide (DCCl); N,Nxe2x80x2-carbonyldiimidazole; POCl3; TiCl4; SO2ClF; Ti(OBu)4; P2I4; Bu3N; benzotriazol-1-yl diethyl phosphate; N,N,Nxe2x80x2,Nxe2x80x2-tetramethyl(succinimido)uronium tetrafluoroborate; and preferably di-iso-propylethyl amine (DIEA) and benzotriazol-1-yloxy-tris(dimethylamino) phosphonium hexafluorophosphate (BOP). 
The synthesis of the amine intermediate 2.0.26 is illustrated in the above reaction scheme. The starting material is a mixture of the tert-butyloxycarbamate intermediates 2.0.24 and 2.0.25. Intermediates 2.0.24 and 2.0.25 are reacted with an acid such as hydrochloric acid or acetic acid with or without a suitable solvent such as dioxane. The reaction is conducted at a temperature between 0 and 100xc2x0 C. for 1 to 16 hours. Acetic acid in the absence of additional solvent at 80xc2x0 for 1.5 hours is preferred. It will be recognized by those skilled in the art that these conditions accomplish both the cyclization to form the desired bicyclic ring system and removal of the tert-butyloxycarbonyl group. It will also be recognized by those skilled in the art that the tert-butyloxycarbonyl group serves as a protecting group for the amine and that other suitable protecting groups can be employed. It will be further recognized that methods for removal of these protecting groups must be compatible with all the functionality present in intermediate 2.0.26. These methods are well-known in the technical literature of the relevant art. For example, see Greene, T. W., Wuts, P. G. M. Protective Group in Organic Synthesis; John Wiley and Sons: New York, 1991.
The above-described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme 6-xcex1, with reference to a particular compound of the present invention: 
An alternative mode for the synthesis of compounds of the Formula (1.0.0) is illustrated in Synthesis Scheme 7 Steps A through C. These steps describe an alternative route to the B component used in the coupling reaction as decribes in Synthesis Scheme 2 Step B. 
The preparation of bromide intermediate 2.0.29 was described in Synthesis Scheme 1 Step A. The intermediate bromide 2.0.29 was reacted with the commercially available imine 2.0.30 in a suitable solvent such as toluene, methylene chloride or DMF with a base such as cesium carbonate, cesium hydroxide or potassium hydroxide in the presence of an additive such as tertabutyl ammonium bromide, tetrabutyl ammonium chloride, or tetraphenylammonium bromide. The reaction was performed at a temperature between xe2x88x9278 and 50xc2x0 C. for a period of 1 to 16 hours. The reaction of the bromide intermediate 2.0.29 with the imine 2.0.30 in toluene at ambient temperature in the presence of tetrabutylammonium bromide for 1 hour was preferred. 
The synthesis of the amine intermediate 2.0.32 is illustrated in the above reaction scheme. The imine intermediate 2.0.31 can be transformed to the amine 2.0.32 by a variety of methods well known to those skilled in the art and described in the literature. For examples, Wolfe, John P.; Ahman, Jens; Sadighi, Joseph P.; Singer, Robert A.; Buchwald, Stephen L.; Tetrahedron Lett.; 1997, 38(36); 6367-6370; and Corey, E. J.; Xu, Feng,; Noe, Mark C.; J. Am. Chem, Soc., 1997, 119, 12414-12415. In the preferred method, intermediate imine 2.0.31 is treated with a mixture of ethyl acetate and hydrochloric acid for three hours at ambient temperature. 
The synthesis of the amide intermediate 2.0.33 is illustrated in the above reaction scheme. The amine with or without a solvent, such as dicloromethane, chloroform, benzene, water or pyridine is reacted with an acid anhydride or acid chloride with or without the addition of a base such as sodium carbonate, pyridine or diisopropyl ethyl amine. The reaction is performed between 0 and 50xc2x0 C. for a period of 1 to 16 hours. The preferred conditions employ dichloromethane and pyridine at ambient temperature for 16 hours.
The above-described synthesis is broadly applicable to the compounds of Formula (1.0.0). In order to make said synthesis even more clear, there is set out below Synthesis Scheme 7-xcex1,: 
The examples which follow further illustrate the compounds, compositions and methods of treatment of the present invention, but are not intended to thereby limit the scope of the present invention. A number abbreviations are used in the following examples in order to conserve space. Although these abbreviations are well known to the artisan, they are set out immediately below for clarity and convenience of the reader: